Compounds for treating neuropsychiatric conditions

ABSTRACT

Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of neuropsychiatric conditions.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.61/139,477, filed Dec. 19, 2008, U.S. Provisional Application No.61/139,498, filed Dec. 19, 2008, U.S. Provisional Application No.61/250,262, filed Oct. 9, 2009; and U.S. Provisional Application No.61/286,317, filed Dec. 14, 2009; each of which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Neuropsychiatric conditions (NCs) are characterized by a variety ofdebilitating affective and cognitive impairments. For example, inschizophrenia, one of the most common psychotic disorders, individualsmay suffer from hallucinations, disorders of movement, and the inabilityto initiate plans, speak, or express emotion. Cognitive deficits inschizophrenia include problems with attention, memory, and the executivefunctions that allow us to plan and organize. Other NCs include, e.g.,mood disorders, age-related cognitive decline, and neurologicaldisorders (e.g., epilepsy and Huntington's disease). The effects of NCsare devastating to the quality of life of those afflicted as well asthat of their families. Moreover, NCs impose an enormous health careburden on society. A number of NCs, as well as other conditions thataffect cognitive function, have been associated with alterations in themorphology and/or density of dendritic spines, membranous protrusionsfrom dendritic shafts of neurons that serve as highly specializedstructures for the formation, maintenance, and function of synapses.

SUMMARY OF THE INVENTION

Described herein are compounds, compositions and methods for treating anindividual suffering from a neuropsychiatric condition (e.g.,schizophrenia, Fragile X Syndrome (FXS), clinical depression,age-related cognitive decline, Mild Cognitive Impairment, Huntington'sdisease, Parkinson's disease, Alzheimer's disease, epilepsy, autismspectrum disorders, mental retardation, Down's syndrome or the like) byadministering to an individual a pharmaceutical composition comprising atherapeutically effective amount of an inhibitor of a p21-activatedkinase (PAK), e.g., an inhibitor of PAK1, PAK2, PAK3 or PAK-4, asdescribed herein. PAK activation is shown to play a key role in spinemorphogenesis. In some instances, attenuation of PAK activity reduces,prevents or reverses defects in spine morphogenesis. In someembodiments, inhibitors of one or more of Group I PAKs (PAK1, PAK2and/or PAK3) and/or Group II PAKs (PAK-4, PAK5 and/or PAK6) areadministered to rescue defects in spine morphogenesis in individualssuffering from a condition in which dendritic spine morphology, density,and/or function are aberrant, including but not limited to abnormalspine density, spine size, spine shape, spine plasticity, spine motilityor spine plasticity.

Provided herein, in some embodiments, are compounds having the structureof Formula V or pharmaceutically acceptable salt or N-oxide thereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, or halogen;    -   R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰,        N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   Q is substituted or unsubstituted cycloalkyl or heterocycloalkyl        fused to ring A;    -   ring A is substituted or unsubstituted aryl or heteroaryl        substituted with 0-4 R⁴;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂), —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkoxy, substituted or unsubstituted            heteroalkyl, substituted or unsubstituted cycloalkyl or            substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8;        provided that when Q is unsubstituted indane,        tetrahydronaphthalene or fluorene, and R⁶ is H, ring B is not        unsubstituted phenyl and R⁵ is not para substituted piperidinyl,        pyrazolyl or methylpiperazinyl.

In some embodiments, the compound of Formula V has the structure ofFormula VI:

-   -   wherein:    -   each of Y³, Y⁴ and Y⁵ are independently a bond, O, N—R^(1a),        CR¹R², SO₂, or C═O;    -   R^(1a) is H or substituted or unsubstituted alkyl;    -   R¹ and R² are each independently H, halogen, —CN, —NO₂, —OH,        —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,        —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,        —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl;    -   s is 0-4.

In some embodiments, the compound of Formula V has the structure ofFormula VII:

-   -   wherein:    -   ring A is an aryl or heteroaryl substituted with R⁴;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl;            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroary, or two R¹⁰                together with the nitrogen to which they are attached                form a heterocycle;        -   each R¹¹ is independently hydrogen, halogen, —CN, —NO₂, —OH,            —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl; or two R¹¹ together with the carbon atom            to which they are attached form C═O;    -   s is 0-4;    -   k is 1-4;    -   z is 0 or 1;    -   u is 1, 2 or 3;    -   provided that z+u≠1;    -   ring B is an aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8;    -   R⁶ is H, or halogen;    -   R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰,        N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of Formula V, VI or VII, ring A is heteroaryl ringcomprising 1-3 nitrogen atoms, an oxygen atom, a sulfur atom, or anycombination thereof. In some embodiments of Formula V, VI or VII, ring Ais a phenyl ring.

In some embodiments, a compound of Formula VII has a structure ofFormula VIIA, Formula VIIB, Formula VIIC, Formula VIID, Formula VIIE,Formula VIIF, Formula VIIG or Formula VIIH:

In some embodiments of Formula VII, R¹¹ is H, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy or)N(R¹⁰)₂. Insome embodiments of Formula VII, R¹¹ is H. In some embodiments ofFormula VII, each R⁴ is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl. In some embodiments of Formula VII, each R⁴ isindependently Cl, F, CF₃ or OMe.

Provided herein, in some embodiments, are compound having the structureof Formula VIII or pharmaceutically acceptable salt or N-oxide thereof:

-   -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkoxy,        —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted aryl        or substituted or unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl, or R¹ and R² together        with the carbon to which they are attached form a C₃-C₆        cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R⁴;    -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H,        —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,        —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)²,        —NR¹⁰C(═O)R¹⁰, —N R¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted        or unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl;        -   R⁸ is H or substituted or unsubstituted alkyl;        -   R⁹ is substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted aryl            or substituted or unsubstituted heteroaryl        -   each R¹⁰ is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl, or two R¹⁰ together with the atoms to which they            are attached form a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8;    -   provided that when s is zero, then R² is not methyl.

In some embodiments of Formula VIII,

-   -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkoxy,        —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted aryl        or substituted or unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl, or R¹ and R² together        with the carbon to which they are attached form a C₃-C₆        cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R³ and R⁴;        -   R³ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰—N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃,            —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,            —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,            —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,            —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,            substituted or unsubstituted alkoxy, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            cycloalkyl or substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8.

In some embodiments of Formula VIII, R³ is halogen, —CN, —NO₂, —OH,—OCF₃, —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl. In some embodiments ofFormula VIII, R³ is a chiral sulfoxide and Q is:

In some embodiments, a compound of Formula VIII has the structure ofFormula VIIIA or Formula VIIIB:

In some embodiments, the compound of Formula VIII has the structure ofFormula (IX):

wherein:

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl; and    -   R³ is halogen, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, SR⁸,        —S(═O)R⁹, or —S(═O)₂R⁹, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl.

In some embodiments of Formula VIII, R³ is F, Cl, SCF₃, CF₃, OMe, (R) or(S) —S(═O)R⁹ or —S(O)₂R⁹.

In some embodiments, the compound of Formula IX has the structure ofFormula (IXA) or Formula (IXB):

Also provided herein, in some embodiments, are compound having thestructure of Formula X or pharmaceutically acceptable salt or N-oxidethereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —N(R¹⁰)₂, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ and R² are each independently H or substituted or        unsubstituted alkyl; or R¹ and R² together with the carbon to        which they are attached form a C₃-C₆ cycloalkyl ring;        -   p is 1, 2 or 3;        -   ring A is aryl substituted with R³ and R⁴;        -   R³ is a substituted or unsubstituted heteroaryl, substituted            or unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl attached to ring A via a carbon atom;            -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃,                —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,                —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,                —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,                —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,                substituted or unsubstituted alkoxy, substituted or                unsubstituted heteroalkyl, substituted or unsubstituted                cycloalkyl or substituted or unsubstituted                heterocycloalkyl;                -   R⁸ is H or substituted or unsubstituted alkyl;                -   R⁹ is substituted or unsubstituted alkyl,                    substituted or unsubstituted cycloalkyl, substituted                    or unsubstituted aryl or substituted or                    unsubstituted heteroaryl                -   each R¹⁰ is independently H, substituted or                    unsubstituted alkyl, substituted or unsubstituted                    cycloalkyl, substituted or unsubstituted aryl or                    substituted or unsubstituted heteroaryl, or two R¹⁰                    together with the atoms to which they are attached                    form a heterocycle;        -   s is 0-4;        -   ring B is aryl or heteroaryl substituted with R⁵;            -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,                —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,                —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,                —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂,                substituted or unsubstituted alkyl, substituted or                unsubstituted alkoxy, substituted or unsubstituted                heteroalkyl, substituted or unsubstituted cycloalkyl or                substituted or unsubstituted heterocycloalkyl;        -   r is 0-8.

In some embodiments of Formula X, Q is:

In some embodiments of Formula X, Q is

In some embodiments of Formula X, R³ is a C₃-C₆ cycloalkyl ring, a5-6-membered heteroaryl ring comprising 1-3 nitrogen atoms, an oxygenatom, a sulfur atom, or any combination thereof, or a 3-6-memberedheterocycloalkyl ring comprising 1-3 nitrogen atoms, an oxygen atom, asulfur atom, or any combination thereof, that is attached to ring via acarbon atom and wherein R³ is further substituted by halogen, cyano,alkyl, alkoxy, —SR⁸, (R) or (S)—S(O)R⁹ or —S(O)₂R⁹. In some embodimentsof Formula X, R¹ and R² are H.

Also provided herein are methods for treating neuropsychiatricconditions comprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula VA orpharmaceutically acceptable salt or N-oxide thereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, or halogen;    -   R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰,        N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   Q is substituted or unsubstituted cycloalkyl or heterocycloalkyl        fused to ring A;    -   ring A is substituted or unsubstituted aryl or heteroaryl        substituted with 0-4 R⁴;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkoxy, substituted or unsubstituted            heteroalkyl, substituted or unsubstituted cycloalkyl or            substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl; and    -   r is 0-8.

Also provided herein are methods for treating neuropsychiatricconditions comprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula VIIIC orpharmaceutically acceptable salt or N-oxide thereof:

-   -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkoxy,        —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted aryl        or substituted or unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl, or R¹ and R² together        with the carbon to which they are attached form a C₃-C₆        cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R⁴;    -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H,        —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,        —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,        —NR¹⁰C(═O)R¹⁰, —N R¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted        or unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl;        -   R⁸ is H or substituted or unsubstituted alkyl;        -   R⁹ is substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted aryl            or substituted or unsubstituted heteroaryl        -   each R¹⁰ is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl, or two R¹⁰ together with the atoms to which they            are attached form a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl; and    -   r is 0-8.

Also provided herein are methods for treating neuropsychiatricconditions comprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula X orpharmaceutically acceptable salt or N-oxide thereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —N(R¹⁰)₂, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ and R² are each independently H or substituted or        unsubstituted alkyl; or R¹ and R² together with the carbon to        which they are attached form a C₃-C₆ cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R³ and R⁴;    -   R³ is a substituted or unsubstituted heteroaryl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl attached to ring A via a carbon atom;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃,            —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,            —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,            —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,            —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,            substituted or unsubstituted alkoxy, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            cycloalkyl or substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula Iis as described herein.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula II, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula IIis as described herein.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula III, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula IIIis as described herein.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula IIIA, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of FormulaIIIA is as described herein.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula IV, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula IVis as described herein.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula V, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula Vis as described above.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula VA, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula VAis as described above.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula VIII, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of FormulaVIII is as described above. Provided herein are pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof Formula VIIIC, or a pharmaceutically acceptable salt or N-oxidethereof, and a pharmaceutically acceptable carrier, wherein the compoundof Formula VIIIC is as described above.

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula X, or apharmaceutically acceptable salt or N-oxide thereof, and apharmaceutically acceptable carrier, wherein the compound of Formula Xis as described above.

Provided herein, in some embodiments, are methods for treatingneuropsychiatric conditions comprising administering to an individual inneed thereof a therapeutically effective amount of a compound of FormulaI wherein compounds of Formula I are as described herein. Providedherein, in some embodiments, are methods for treating neuropsychiatricconditions comprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula II whereincompounds of Formula II are as described herein. Provided herein, insome embodiments, are methods for treating neuropsychiatric conditionscomprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula III whereincompounds of Formula III are as described herein. Provided herein, insome embodiments, are methods for treating neuropsychiatric conditionscomprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula IIIA whereincompounds of Formula IIIA are as described herein. Provided herein, insome embodiments, are methods for treating neuropsychiatric conditionscomprising administering to an individual in need thereof atherapeutically effective amount of a compound of Formula IV whereincompounds of Formula IV are as described herein.

In some embodiments of any of the above methods, compounds of any ofFormulae I-X are inhibitors of p21-activated kinase. In someembodiments, compounds of any of Formulae I-X inhibit one or more ofPAK1, PAK2, PAK3, PAK4, PAK5 or PAK6. In some embodiments of any of theabove methods compounds of any of Formulae I-X inhibit one or more ofPAK1, PAK2 or PAK3. In some embodiments of any of the above methods,compounds of any of Formulae I-X inhibit PAK1 and PAK3. In someembodiments of any of the above methods, compounds of any of FormulaeI-X inhibit PAK1 and PAK2. In some embodiments of any of the abovemethods, compounds of any of Formulae I-X inhibit PAK1, PAK2 and PAK3.In some embodiments of any of the above methods, compounds of any ofFormulae I-X inhibit PAK1 and PAK4. In some embodiments of any of theabove methods, compounds of any of Formulae I-X inhibit PAK1, PAK2, PAK3and PAK4.

In some embodiments of any of the above methods, compounds of any ofFormulae I-X inhibit PAK1. In some embodiments of any of the abovemethods, compounds of any of Formulae I-X inhibit PAK2. In someembodiments of any of the above methods, compounds of any of FormulaeI-X inhibit PAK3. In some embodiments of any of the above methods,compounds of any of Formulae I-X inhibit PAK4.

In some embodiments of any of the above methods, a therapeuticallyeffective amount compounds of any of Formulae I-X causes substantiallycomplete inhibition of one or more Group I p21-activated kinases.

In some embodiments of any of the above methods, a therapeuticallyeffective amount of compounds of any of Formulae I-X causes partial,inhibition of one or more Group I p21-activated kinases.

In some embodiments of any of the above methods, the neuropsychiatriccondition is a psychotic disorder, a mood disorder or cognitiveimpairment.

In some embodiments of any of the above methods, the neuropsychiatriccondition is schizophrenia, Alzheimer's disease, mild cognitiveimpairment, age-related cognitive decline, Parkinson's disease, FragileX Syndrome, autism spectrum disorder, clinical depression, epilepsy,Huntington's disease, mental retardation, Down's syndrome, Niemann-Pickdisease, spongiform encephalitis, Lafora disease, Maple syrup urinedisease, maternal phenylketonuria, Rett's syndrome, atypicalphenylketonuria, cognitive decline associated with menopause or tuberoussclerosis

In some embodiments of any of the above methods, compounds of any ofFormulae I-X modulate dendritic spine morphology or synaptic function.In some embodiments of any of the above methods, compounds of any ofFormulae I-X modulate dendritic spine density. In some embodiments ofany of the above methods, compounds of any of Formulae I-X modulatedendritic spine length. In some embodiments of any of the above methods,compounds of any of Formulae I-X modulate dendritic spine neck diameter.In some embodiments of any of the above methods, compounds of any ofFormulae I-X modulate dendritic spine head volume. In some embodimentsof any of the above methods, compounds of any of Formulae I-X modulatethe ratio of the number of mature spines to the number of immaturespines. In some embodiments of any of the above methods, compounds ofany of Formulae I-X modulate the ratio of the spine head diameter tospine length. In some embodiments of any of the above methods, compoundsof any of Formulae I-X modulate synaptic function.

In some embodiments of any of the above methods, compounds of any ofFormulae I-X normalize or partially normalize aberrant baseline synaptictransmission associated with a neuropsychiatric condition. In someembodiments of any of the above methods, compounds of any of FormulaeI-X normalize or partially normalize aberrant synaptic plasticityassociated with a neuropsychiatric condition. In some embodiments of anyof the above methods, compounds of any of Formulae I-X normalize orpartially normalize aberrant long term depression (LTD) associated witha neuropsychiatric condition. In some embodiments of any of the abovemethods, compounds of any of Formulae I-X normalize or partiallynormalize aberrant long term potentiation (LTP) associated with aneuropsychiatric condition.

In some embodiments of any of the above methods, compounds of any ofFormulae I-X normalize or partially normalize aberrant sensorimotorgating associated with a neuropsychiatric condition. In some embodimentsof any of the above methods, compounds of any of Formulae I-X reduce orreverse negative symptoms associated with a neuropsychiatric condition.In some of such embodiments, the negative symptoms associated with aneuropsychiatric condition are asociality, blunted affect, avolition,alogia, anhedonia or dysphoric mood.

In some embodiments of any of the above methods, compounds of any ofFormulae I-X reduce or reverse cognitive symptoms associated with aneuropsychiatric condition. In some of such embodiments, the cognitivesymptoms associated with a neuropsychiatric condition are impairment inexecutive function, comprehension, inference, decision-making, planning,learning or memory.

In some embodiments of any of the above methods compounds of any ofFormulae I-X halt or delay progression of cognitive impairmentassociated with a neuropsychiatric condition. In some of suchembodiments, the cognitive impariment is mild cognitive impairment. Insome embodiments, the cognitive impairment is associated withAlzheimer's disease.

In some embodiments of any of the above methods, the method furthercomprises administration of a second therapeutic agent that alleviatesone or more symptoms associated with a neuropsychiatric condition.

In some embodiments, the second therapeutic agent is an antipsychoticagent, a cognition enhancer, a Group I mGluR antagonist, a mGluR5antagonist, a mGluR5 potentiator, a nootropic agent, an alpha7 nicotinicreceptor agonist, an allosteric alpha7 nicotinic receptor potentiator, anootropic agent, a trophic agent, an antioxidant, a neuroprotectant, abeta secretase inhibitor, a gamma secretase inhibitor or an Abetaantibody.

In some embodiments, administration of a therapeutically effect amountof compounds of any of Formulae I-X to an individual in need thereofimproves one or more of MATRICS cognition scores, Wisconsin Card Sorttest scores, Mini-Mental State Exam (MMSE) scores, Alzheimer DiseaseAssessment Scale-Cognitive (ADAS-cog) scale scores, ADAS-Behav scores,or Hopkins Verbal Learning Test Revised scores for the individual.

Provided herein are methods for reversing cortical hypofrontalityassociated with a neuropsychiatric condition comprising administering toan individual in need thereof a therapeutically effective amount of acompound of any of Formulae I-X. Provided herein are methods forreducing, stabilizing, or reversing neuronal withering and/or loss ofsynaptic function associated a neuropsychiatric condition comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a compound of any of Formulae I-X. Provided hereinare methods for reducing, stabilizing or reversing atrophy ordegeneration of nervous tissue in the brain associated with aneuropsychiatric condition comprising administering to an individual inneed thereof a therapeutically effective amount of a compound of any ofFormulae I-X.

Provided herein are methods of inhibiting the activity of one or morep21-activated kinases comprising contacting the one or morep21-activated kinases with a compound of any of Formulae I-X. In someembodiments, the one or more p21-activated kinase is contacted with acompound of any of Formulae I-X in vitro. In some embodiments, the oneor more p21-activated kinase is contacted with a compound of any ofFormulae I-X in vivo.

Provided herein is the use of compounds of any of Formulae I-X in themanufacture of a medicament for the treatment of a neuropsychiatriccondition.

As used herein, compounds of any of Formulae I-X or compound of FormulaI-X includes compounds of Formula I, II, III, IIIA, IV, V, VA, VI, VII,VIII, VIIIA, VIIIB, VIIIC, IX, and X.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 describes illustrative shapes of dendritic spines.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are methods for treatment of neuropsychiatric conditionsby administration of inhibitors of certain p21 activated kinases toindividuals in need thereof. Such kinase inhibitors are inhibitors ofone or more of PAK1, PAK2, PAK3, PAK4, PAK5 or PAK6 kinases. In certainembodiments, the individual has been diagnosed with or is suspected ofsuffering from a neuropsychiatric and/or neurodegenerative disease orcondition that is mediated by p21 activated kinases. In some instances,provided herein are methods for treating conditions characterized byabnormal dendritic spine morphology and/or spine density and/or spinelength and/or spine thickness.comprising.inhibiting PAK activity byadministration of a therapeutically effective amount of a PAK inhibitorto an individual diagnosed with or suspected of suffering from a NC(e.g., pscyhotic disorders, mood disorders, age-related cognitivedecline, epilepsy, Huntington's disease, schizophrenia, Alzheimer'sdisease, Parkinson's disease, mental retardation, Down's syndrome,Niemann-Pick disease, spongiform encephalitis, Lafora disease, Maplesyrup urine disease, maternal phenylketonuria, atypical phenylketonuria,cognitive decline associated with menopause, Rett's syndrome andtuberous sclerosis).

A number of NCs are characterized by abnormal dendritic spinemorphology, spine size, spine plasticity and/or spine density asdescribed in a number of studies referred to herein. PAK kinase activityhas been implicated in spine morphogenesis, maturation, and maintenance.See, e.g., Kreis et al (2007), J Biol Chem, 282(29):21497-21506; Hayashiet al (2007), Proc Natl Acad Sci U S A., 104(27):11489-11494, Hayashi etal (2004), Neuron, 42(5):773-787; Penzes et al (2003), Neuron,37:263-274. In some embodiments, inhibition or partial inhibition of oneor more PAKs normalizes aberrant dendritic spine morphology and/orsynaptic function. NCs that are treated by the methods described hereininclude, but are not limited to, schizophrenia, psychotic disorders,mood disorders, age-related cognitive decline, epilepsy, Huntington'sdisease, Alzheimer's disease, Parkinson's disease, mental retardation,Down's syndrome, Niemann-Pick disease, spongiform encephalitis, Laforadisease, Maple syrup urine disease, maternal phenylketonuria, atypicalphenylketonuria, cognitive decline associated with menopause, Rett'ssyndrome and tuberous sclerosis.

In some instances, NCs are associated with abnormal dendritic spinemorphology, spine size, spine plasticity, spine motility, spine densityand/or abnormal synaptic function. In some instances, activation of oneor more of PAK1, PAK2, PAK3, PAK4, PAK5 and/or PAK6 kinases isimplicated in defective spine morphogenesis, maturation, andmaintenance. Described herein are methods for suppressing or reducingPAK activity (e.g., by administering a PAK inhibitor for rescue ofdefects in spine morphology, size, plasticity spine motility and/ordensity) associated with neuropsychiatric conditions as describedherein. Accordingly, in some embodiments, the methods described hereinare used to treat an individual suffering from a neuropsychiatricdisorder wherein the disease is associated with abnormal dendritic spinedensity, spine size, spine plasticity, spine morphology, spineplasticity, or spine motility.

In some embodiments, any inhibitor of one or more p21-activated kinasesdescribed herein modulates abnormalities in dendritic spine morphologyand/or synaptic function that are associated with neuropsychiatricconditions. In some embodiments, modulation of dendritic spinemorphology and/or synaptic function alleviates or reverses cognitiveimpairment and/or negative behavioral symptoms (e.g., social withdrawal,anhedonia or the like) associated with NCs. In some embodiments,modulation of dendritic spine morphology and/or synaptic function haltsor delays progression of cognitive impairment and/or loss of bodilyfunctions associated with NCs.

In some instances, cellular changes in brain cells contribute topathogenesis of a neuropsychiatric condition. In some instances, anabnormality in dendritic spine density in the brain contributes to thepathogenesis of a neuropsychiatric condition. In some instances, anabnormality in dendritic spine morphology contributes to thepathogenesis of a neuropsychiatric condition. In some instances, anabnormality in the pruning of dendritic spines or synapses duringpuberty contributes to the pathogenesis of a neuropsychiatric condition.In some instances, an abnormality in synaptic function contributes tothe pathogenesis of a neuropsychiatric condition. In some instances,activation of one or more PAKs is associated with an abnormality indendritic spine density and/or dendritic morphology and/or synapticfunction and contributes to the pathogenesis of a neuropsychiatriccondition. In some instances, modulation of PAK activity (e.g.,attenuation, inhibition or partial inhibition of PAK activity) reversesor reduces abnormalities in dendritic spine morphology and/or dendriticspine density and/or synaptic function. In certain embodiments,modulation of activity of one or more Group I PAKs (one or more of PAK1,PAK2 and/or PAK3) reverses or reduces abnormalities in dendritic spinemorphology and/or dendritic spine density and/or synaptic functionassociated with neuropsychiatric conditions.

Abnormal dendritic spine morphology and/or density have been found in anumber of NCs as described below. Accordingly, in some embodiments, themethods described herein are used to treat an individual suffering froma neuropsychiatric condition that is associated with abnormal dendriticspine density, spine size, spine plasticity, spine morphology, spineplasticity, or spine motility. In some embodiments, the methodsdescribed herein are used to treat an individual suffering from apsychotic disorder, as described in, by way of example, Example 124 andExample 128 herein. Examples of psychotic disorders include, but are notlimited to, schizophrenia, schizoaffective disorder, schizophreniformdisorder, brief psychotic disorder, delusional disorder, sharedpsychotic disorder (Folie a Deux), substance induced psychosis, andpsychosis due to a general medical condition. See, e.g., Black et al.(2004), Am J Psychiatry, 161:742-744; Broadbelt et al. (2002), SchizophrRes, 58:75-81; Glantz et al. (2000), Arch Gen Psychiatry 57:65-73; andKalus et al. (2000), Neuroreport, 11:3621-3625. In some instances,aberrant spine morphogenesis is associated with negative symptoms (e.g.,asociality, blunted affect, avolition, alogia, anhedonia or dysphoricmood), and/or cognitive impairment symptomatic of schizophrenia. In someinstances, aberrant spine morphogenesis is associated with positivesymptoms and behavioral changes (e.g., social withdrawal,depersonalization, loss of appetite, loss of hygiene, delusions,hallucinations, the sense of being controlled by outside forces or thelike)symptomatic of schizophrenia.

In some embodiments, the methods described herein are used to treat anindividual suffering from a mood disorder. Examples of mood disordersinclude, but are not limited to, clinical depression as described in,for example, Example 126 herein, bipolar disorder, cyclothymia, anddysthymia. See, e.g., Hajszan et al (2005), Eur J Neurosci,21:1299-1303; Law et al (2004) Am J Psychiatry, 161(10):1848-1855;Norrholm et al. (2001), Synapse, 42:151-163; and Rosoklija et al.(2000), Arch Gen Psychiatry, 57:349-356.

In some embodiments, the methods described herein are used to treat anindividual suffering from neurodegenerative disorders (e.g., age-relatedcognitive decline, Parkinson's disease, Alzheimer's disease (asdescribed in, for example, Example 130 herein) or the like). See, e.g.,Dickstein et al (2007), Aging Cell, 6:275-284; and Page et al. (2002),Neuroscience Letters, 317:37-41. In some embodiments, the methodsdescribed herein are used to treat an individual suffering from orsuspected of having mild cognitive impairment (MCI). In someembodiments, the methods described herein are used to halt or delayprogression of mild cognitive impairment (MCI) to early dementia,mid-stage dementia or late stage dementia in an individual sufferingfrom or suspected of having mild cognitive impairment (MCI). In someinstances, Alzheimer's disease is associated with abnormal dendriticspine morphology, spine size, spine plasticity, spine motility, spinedensity and/or abnormal synaptic function. In some instances, solubleAbeta dimers and/or oligomers increase PAK kinase activity at thesynapse. In some instances, Abeta plaques and/or insoluble Abetaaggregates increase PAK kinase activity at the synapse. In someinstances, increased PAK kinase activity is associated with defectivespine morphogenesis, maturation, and maintenance. In some instances, PAKinhibitors reverse defects in synaptic function and plasticity in apatient diagnosed with Alzheimer's disease before Abeta plaques can bedetected. In some embodiments, PAK inhibitors reverse defects insynaptic morphology, synaptic transmission and/or synaptic plasticityinduced by soluble Abeta dimers and/or oligomers. In some embodiments,PAK inhibitors reverse defects in synaptic morphology, synaptictransmission and/or synaptic plasticity induced by Abeta oligomersand/or Abeta-containing plaques.

In some embodiments, the methods described herein are used to treat anindividual suffering from epilepsy as described in, for example, Example127 herein. See, e.g., Wong (2005), Epilepsy and Behavior, 7:569-577;Swann et al (2000), Hippocampus, 10:617-625; and Jiang et al (1998), JNeurosci, 18(20):8356-8368.

In some embodiments, the methods described herein are used to treat anindividual suffering from Parkinson's Disease or Huntington's Disease.See, e.g., Neely et al (2007), Neuroscience, 149(2):457-464; Spires etal (2004), Eur J Neurosci, 19:2799-2807; Klapstein et al (2001), JNeurophysiol, 86:2667-2677; Ferrante et al (1991), J Neurosci,11:3877-3887; and Graveland et al (1985), Science, 227:770-773.

In some embodiments, the methods described herein are used to treat anindividual suffering from mental retrdation, Fragile X syndrome, autismspectrum disorders or the like.

In some embodiments, the methods described herein are used to treat anindividual suffering from mental retardation, Down's syndrome, Epilepsy,Niemann-Pick disease, spongiform encephalitis, Lafora disease, Maplesyrup urine disease, maternal to phenylketonuria, atypicalphenylketonuria, cognitive decline associated with menopause, Rett'ssyndrome and tuberous sclerosis.

In some instances, development of an NC is associated with a geneticcomponent. Certain risk alleles and genes that have been identified forNCs. For example, for Alzheimer's disease, risk alleles and genesinclude mutations in Amyloid Precursor Protein (APP), mutations inpresenilin 1 and 2, the epsilon4 allele, the 91 bp allele in thetelomeric region of 12q, Apolipoprotein E-4 (APOE4) gene, SORL1 gene,reelin gene or the like. For example, in some instances, development ofschizophrenia is associated with mutations in the DISC1 gene. In someinstances, several risk alleles or genes are involved in etiology of aNC. In some instances, NCs run in families and there is a predispositionor vulnerability to the illness. In some instances, a combination ofgenetic, familial and environmental factors play a role in manifestationof disease symptoms. In some instances, mutations in genes resulting ina predisposition to a NC leads to early-onset of the disease.

Dendritic Spines

A dendritic spine is a small membranous protrusion from a neuron'sdendrite that serves as a specialized structure for the formation,maintenance, and/or function of synapses. Dendritic spines vary in sizeand shape. In some instances, spines have a bulbous head (the spinehead) of varying shape, and a thin neck that connects the head of thespine to the shaft of the dendrite. In some instances, spine numbers andshape are regulated by physiological and pathological events. In someinstances, a dendritic spine head is a site of synaptic contact. In someinstances, a dendritic spine shaft is a site of synaptic contact.

In some instances, mature spines have variably-shaped bulbous tips orheads, ˜0.5-2 μm in diameter, connected to a parent dendrite by thinstalks 0.04-1 μm long. In some instances, spine density ranges from 1 to10 spines per micrometer length of dendrite, and varies withmaturational stage of the spine and/or the neuronal cell. In someinstances, dendritic spine density ranges from 1 to 40 spines per 10micrometer in medium spiny neurons. In some instances, small-headedspines have head volume <0.05 μm³) medium-size headed spines have headvolumes of 0.05 μm³-0.1 μm³ and large-headed spines have head volumesof >0.1 μm³.

FIG. 1 shows examples of different shapes of dendritic spines. Dendriticspines are “plastic.” In other words, spines are dynamic and continuallychange in shape, volume, and number. In some instances, spines change inshape, volume, length, thickness or number in a few hours. In someinstances, spines change in shape, volume, length, thickness or numberoccurs within a few minutes. In some instances, spines change in shape,volume, length, thickness or number occurs in response to synaptictransmission and/or induction of synaptic plasticity. By way of example,dendritic spines are headless (filopodia as shown, for example, in FIG.1 a), thin (for example, as shown in FIG. 1 b), stubby (for example asshown in FIG. 1 c), mushroom-shaped (have door-knob heads with thicknecks, for example as shown in FIG. 1 d), ellipsoid (have prolatespheroid heads with thin necks, for example as shown in FIG. 1 e),flattened (flattened heads with thin neck, for example as shown in FIG.10 or branched (for example as shown in FIG. 1 g). In some instances,the shape of the dendritic spine head determines synpatic function. Insome instances, dendritic spines with larger spine head diameter formmore stable synapses compared with dendritic spines with smaller headdiameter. In some instances, a mushroom-shaped spine head is associatedwith normal or partially normal synaptic function. In some instances, amushroom-shaped spine head is a healthier spine head (e.g., havingnormal or partially normal synapses) compared to a spine head that isstubby or flat or thin. In some instances, inhibition or partialinhibition of PAK activity results in an increase in spine head diameterand/or spine head volume and/or reduction of spine length, therebynormalizing or partially normalizing synaptic function in individualssuffering or suspected of suffering from a neuropsychiatric condition.

p21-Activated Kinases (PAKs)

The PAKs constitute a family of serine-threonine kinases that iscomposed of “conventional”, or Group I PAKs, that includes PAK1, PAK2,and PAK3, and “non-conventional”, or Group II PAKs, that includes PAK4,PAK5, and PAK6. See, e.g., Zhao et al., (2005), Biochem J, 386:201-214.These kinases function downstream of the small GTPases Rac and/or Cdc42to regulate multiple cellular functions, including dendriticmorphogenesis and maintenance (see, e.g., Ethell et al (2005), Prog inNeurobiol, 75:161-205; Penzes et al (2003), Neuron, 37:263-274),motility, morphogenesis, angiogenesis, and apoptosis, (see, e.g., Bokochet al., 2003, Annu. Rev. Biochem., 72:743; and Hofmann et al., 2004, J.Cell Sci., 117:4343). GTP-bound Rac and/or Cdc42 bind to inactive PAK,releasing steric constraints imposed by a PAK autoinhibitory domainand/or permitting PAK phosphorylation and/or activation. Numerousphosphorylation sites have been identified that serve as markers foractivated PAK.

In some instances, upstream effectors of PAK include, but are notlimited to, TrkB receptors; NMDA receptors; adenosine receptors;estrogen receptors; integrins, EphB receptors; CDK5, FMRP; Rho-familyGTPases, including Cdc42, Rac (including but not limited to Rac1 andRac2), Chp, TC10, and Wrnch-1; guanine nucleotide exchange factors(“GEFs”), such as but not limited to GEFT, α-p-21-activated kinaseinteracting exchange factor (αPIX), Kalirin-7, and Tiam1; Gprotein-coupled receptor kinase-interacting protein 1 (GIT1), andsphingosine.

In some instances, downstream effectors of PAK include, but are notlimited to, substrates of PAK kinase, such as Myosin light chain kinase(MLCK), regulatory Myosin light chain (R-MLC), Myosins I heavy chain,myosin II heavy chain, Myosin VI, Caldesmon, Desmin, Op18/stathmin,Merlin, Filamin A, LIM kinase (LIMK), Ras, Raf, Mek, p47phox, BAD,caspase 3, estrogen and/or progesterone receptors, RhoGEF, NETI, Gαz,phosphoglycerate mutase-B, RhoGD1, prolactin, p41Arc, cortactin and/orAurora-A (See, e.g., Bokoch et al., 2003, Annu. Rev. Biochem., 72:743;and Hofmann et al., 2004, J. Cell Sci., 117:4343). Other substances thatbind to PAK in cells include CIB; sphingolipids; lysophosphatidic acid,G-protein β and/or γ subunits; PIX/COOL; GIT/PKL; Nef; Paxillin; NESH;SH3-containing proteins (e.g. Nck and/or Grb2); kinases (e.g. Akt, PDK1,PI 3-kinase/p85, Cdk5, Cdc2, Src kinases, Abl, and/or protein kinase A(PKA)); and/or phosphatases (e.g. phosphatase PP2A, POPX1, and/orPOPX2).

PAK Inhibitors

Described herein are PAK inhibitors that treat one or more symptomsassociated with neuropsychiatric conditions. Also described herein arepharmaceutical compositions comprising a PAK inhibitor (e.g., a PAKinhibitor compound described herein) for reversing or reducing one ormore of cognitive impairment and/or dementia and/or negative symptomsand/or positive symptoms associated with NCs. Also described herein arepharmaceutical compositions comprising a PAK inhibitor (e.g., a PAKinhibitor compound described herein) for halting or delaying theprogression of cognitive impairment and/or dementia and/or negativesymptoms and/or positive symptoms associated with NCs. Described hereinis the use of a PAK inhibitor for manufacture of a medicament fortreatment of one or more symptoms of a neuropsychiatric condition.

In some embodiments, the PAK inhibitor is a Group I PAK inhibitor thatinhibits, for example, one or more Group I PAK polypeptides, forexample, PAK1, PAK2, and/or PAK3. In some embodiments, the PAK inhibitoris a PAK1 inhibitor (e.g., compound 2, 7, 12, 36, 49, 55, 56, 58, 75,80, 98 or the like). In some embodiments, the PAK inhibitor is a PAK2inhibitor. In some embodiments, the PAK inhibitor is a PAK3 inhibitor.In some embodiments, the PAK inhibitor is a mixed PAK1/PAK3 inhibitor.In some embodiments, the PAK inhibitor is a mixed PAK1/PAK2 inhibitor(e.g., compound 21, 33, 43 or the like). In some embodiments, the PAKinhibitor is a mixed PAK1/PAK-4 inhibitor (e.g., compound 18, 59, 61,94, 106, 111, 113 or the like). In some embodiments, the PAK inhibitoris a mixed PAK1/PAK2/PAK-4 inhibitor (e.g., compound 22, 51, 57, 66 orthe like). In some embodiments, the PAK inhibitor is a mixedPAK1/PAK2/PAK3/PAK-4 inhibitor (e.g., compound 13, 14, 15, 19, 23, 27,44, 45, 46, 53, 60, 62, 63, 65, 69, 71, 72, 73, 74, 78, 79, 81, 91 orthe like). In some embodiments, the PAK inhibitor inhibits all threeGroup I PAK isoforms (PAK1, 2 and PAK3) with equal or similar potency(e.g., compound 64, 68, 77, 84, 86, 119, 120, 121 or the like). In someembodiments, the PAK inhibitor is a Group II PAK inhibitor that inhibitsone or more Group II PAK polypeptides, for example PAK-4, PAK5, and/orPAK6. In some embodiments, the PAK inhibitor is a PAK4 inhibitor. Insome embodiments, the PAK inhibitor is a PAK5 inhibitor. In someembodiments, the PAK inhibitor is a PAK6 inhibitor.

In certain embodiments, a PAK inhibitor described herein reduces orinhibits the activity of one or more of PAK1, PAK2, PAK3, and/or PAK4while not affecting the activity of PAK5 and PAK6. In some embodiments,a PAK inhibitor described herein reduces or inhibits the activity of oneor more of PAK1, PAK2 and/or PAK3 while not affecting the activity ofPAK4, PAK5 and/or PAK6. In some embodiments, a PAK inhibitor describedherein reduces or inhibits the activity of one or more of PAK1, PAK2,PAK3, and/or one or more of PAK4, PAK5 and/or PAK6. In some embodiments,a PAK inhibitor described herein is a substantially complete inhibitorof one or more PAKs. As used herein, “substantially complete inhibition”means, for example, >95% inhibition of one or more targeted PAKs. Inother embodiments, “substantially complete inhibition” means, forexample, >90% inhibition of one or more targeted PAKs. In some otherembodiments, “substantially complete inhibition” means, forexample, >80% inhibition of one or more targeted PAKs. In someembodiments, a PAK inhibitor described herein is a partial inhibitor ofone or more PAKs. As used herein, “partial inhibition” means, forexample, between about 40% to about 60% inhibition of one or moretargeted PAKs. In other embodiments, “partial inhibition” means, forexample, between about 50% to about 70% inhibition of one or moretargeted PAKs. As used herein, where a PAK inhibitor substantiallyinhibits or partially inhibits the activity of a certain PAK isoformwhile not affecting the activity of another isoform, it means, forexample, less than about 10% inhibition of the non-affected to isoformwhen the isoform is contacted with the same concentration of the PAKinhibitor as the other substantially inhibited or partially inhibitedisoforms. In other instances, where a PAK inhibitor substantiallyinhibits or partially inhibits the activity of a certain PAK isoformwhile not affecting the activity of another isoform, it means, forexample, less than about 5% inhibition of the non-affected isoform whenthe isoform is contacted with the same concentration of the PAKinhibitor as the other substantially inhibited or partially inhibitedisoforms. In yet other instances, where a PAK inhibitor substantiallyinhibits or partially inhibits the activity of a certain PAK isoformwhile not affecting the activity of another isoform, it means, forexample, less than about 1% inhibition of the non-affected isoform whenthe isoform is contacted with the same concentration of the PAKinhibitor as the other substantially inhibited or partially inhibitedisoforms.

Provided herein, in certain embodiments, are compounds of Formula I:

-   -   wherein:    -   R¹ is H, substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl; or substituted or unsubstituted        heterocycloalkyl;    -   R², R³ are independently H, halo, hydroxy, cyano, amino or        substituted or unsubstituted alkyl;    -   each R⁴ is halo, hydroxy, cyano, substituted or unsubstituted        alkyl, substituted or unsubstituted alkoxy, substituted or        unsubstituted alkylamino, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        cycloalkyl, or substituted or unsubstituted heterocycloalkyl;    -   n is 0-5;    -   Q¹, Q², Q³, Q⁴, Q⁵ are each independently N or C—R^(4a); wherein        R^(4a) is H or R⁴; provided that at least two of Q¹, Q², Q³, Q⁴,        Q⁵ are C—R^(4a);    -   Q⁶ is N or C—R^(4b); wherein R^(4b) is H, halo, hydroxy, cyano,        substituted or unsubstituted alkyl, or substituted or        unsubstituted alkoxy;    -   W is O, N—R⁵ or C(R⁵)₂, wherein each R⁵ is independently H,        hydroxy, substituted or unsubstituted alkyl; or two R⁵ taken        together are (═O) or (═NR⁶); wherein R⁶ is H, hydroxy,        substituted or unsubstituted alkyl, or substituted or        unsubstituted alkoxy;    -   provided that when R² and R³ are H, R¹ is cyclopentyl, W is NH,        n is 1, Q¹, Q², Q⁴, Q⁵ are CH, Q³ is CR⁴ and Q⁶ is N, R⁴ is not        p4-methylpiperazin-1-yl;        or a pharmaceutically acceptable salt thereof.

In some embodiments, W is N—R⁵. In some embodiments, Q³ is C—R^(4a). Insome embodiments, R² and R³ are independently H, or halo. In someembodiments, R¹ is H or substituted or unsubstituted cycloalkyl. In someembodiments, R¹ is substituted or unsubstituted cyclopropane,substituted or unsubstituted cyclobutane, substituted or unsubstitutedcyclopentane, or substituted or unsubstituted cyclohexane. In someembodiments, each R⁴ is halo, cyano, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylamino or substituted or unsubstituted heteroalkyl. In someembodiments, R⁴ is substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl. In some embodiments, R⁴is substituted or unsubstituted cyclopropane, substituted orunsubstituted cyclobutane, substituted or unsubstituted cyclopentane,substituted or unsubstituted cyclohexane, substituted or unsubstitutedpyran, substituted or unsubstituted tetrahydrofuran, substituted orunsubstituted pyrrolidine, substituted or unsubstituted piperidine,substituted or unsubstituted morpholine, substituted or unsubstitutedpyrrolidinone or substituted or unsubstituted piperidinone.

In some embodiments, Q⁶ is N. In some embodiments of Formula I, W is NH.In some embodiments, compounds of Formula I are p21-activated kinaseinhibitors.

In certain embodiments, compounds of Formula I are as described in Table1.

TABLE 1

Compound No. Q¹ Q² Q⁴ Q⁵ Q⁶ W R¹ R² R³ R⁴ 1-1 N CH CH CH N NH

H OH

1-2 CH CH CH CH N NH

H H

1-3 CH CH CH CH N NH

H H

1-4 CH N CH CH N NH

Me H

1-5 N N CH CH N O

H Me

1-6 CH CH CH CH N NH

H H

1-7 CH CH CH CH N NH

H Me

1-8 CH CH CH CH N NH

H H

1-9 CH N N CH N NH

Cl H

1-10 CH CH CH CH N NH Me H H

1-11 CH CH CH CH N NH H H H

1-12 CH CH CH CH N NH

Me H

1-13 CH CH CH CH N NH

H H

1-14 CH CH CH CH N NH

H H

1-15 N CH CH N CH NH

H CN

1-16 CH CH CH CH N NH

H H

1-17 CH CH CH CH N NH

H H

1-18 CH N CH CH N O

Me H

1-19 CH CH CH CH N NH

H H

1-20 CH C—F CH CH N C═O

H Me

1-21 CH C—F CH CH N NH

Me H

1-22 CH CH CH CH N NH

H H

Also provided herein, in certain embodiments, are compounds of FormulaII:

-   -   wherein:        -   R⁶ is H, halo, hydroxy, cyano, substituted or unsubstituted            alkyl, or substituted or unsubstituted alkoxy,        -   R⁷ is substituted or unsubstituted alkyl, substituted or            unsubstituted alkoxy, substituted or unsubstituted            alkylamino, C(═O)—N(R¹⁰)₂, C(═O)—O(R¹⁰)₂, S(O)_(m)—N(R¹⁰)₂,            N(R¹⁰)₂C(═O)R¹⁰, OC(═O)(R¹⁰), N(R¹⁰)₂S(O)_(m)R¹⁰,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted heteroaryl,            substituted or unsubstituted cycloalkyl, or substituted or            unsubstituted heterocycloalkyl; wherein each R¹⁰ is            independently H, substituted or unsubstituted alkyl;            substituted or unsubstituted cycloalkyl, or substituted or            unsubstituted alkylcycloalkyl; and m is 1-2;        -   R⁸ is H, halo, hydroxy, cyano, substituted or unsubstituted            alkyl, substituted or unsubstituted alkoxy, substituted or            unsubstituted alkylamino, C(═O)—N(R¹⁰)₂, C(═O)—O(R¹⁰,            S(O)_(m)—NR¹⁰)₂, N(R¹⁰)₂C(═O)R¹⁰, OC(═O)(R¹⁰),            N(R¹⁰)₂S(O)_(m)R¹⁰;        -   R⁹ is substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            cycloalkyl, or substituted or unsubstituted            heterocycloalkyl;        -   Q⁷, Q⁸ are independently N or C—R⁶;        -   X is O, N—R¹¹ or C(R¹¹)₂, wherein each R¹¹ is independently            H, hydroxy, substituted or unsubstituted alkyl; or two R¹¹            taken together are (═O) or (═NR¹²); wherein R¹² is H,            hydroxy, substituted or unsubstituted alkyl, or substituted            or unsubstituted alkoxy;        -   provided that when Q⁸ is N, Q⁷ is CH, R⁷, R⁸ are alkoxy, and            R⁶ is cyano, R⁹ is not 2,4-dichloroanilino;            or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula II, X is N—R¹¹. In some embodiments, oneof Q² and Q³ is N and the other is CH. In some embodiments, R⁶ is H,halo, hydroxy, or cyano. In some embodiments, R⁷ is substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylamino, C(═O)—N(R¹⁰)₂, S(O)_(m)—N(R¹⁰)₂, orsubstituted or unsubstituted heteroalkyl. In some embodiments, R⁷ issubstituted or unsubstituted alkoxy, substituted or unsubstitutedalkylamino, or substituted or unsubstituted heteroalkyl. In someembodiments, R⁸ is H, halo, cyano, or substituted or unsubstitutedalkoxy.

In some embodiments, R⁹ is substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, or substituted or unsubstituted heterocycloalkyl. In someembodiments, R⁹ is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl. In some embodiments, R⁹ is substituted orunsubstituted phenyl, substituted or unsubstituted pyridinyl,substituted or unsubstituted pyrimidinyl, substituted or unsubstitutedpyrazinyl, substituted or unsubstituted thienyl, substituted orunsubstituted pyrazolyl, substituted or unsubstituted imidazolyl,substituted or unsubstituted triazolyl, substituted or unsubstitutedoxazolyl, substituted or unsubstituted isoxazolyl, or substituted orunsubstituted thiazolyl.

In some embodiments of Formula II, Q⁷ is CH and Q⁸ is N. In someembodiments, Q⁷ is N and Q⁸ is CH. In some embodiments, X is NH. In someembodiments, compounds of Formula II are p21-activated kinaseinhibitors.

In certain embodiments, compounds of Formula II are as described inTable 2.

TABLE 2

Compound No. Q⁷ Q⁸ R⁶ R⁷ R⁸ R⁹ X 2-1 N CH Cl

OMe

NH 2-2 N CH OMe

O(isopropyl)

NH 2-3 CH N CN

OMe

NH 2-4 CH N CN

OMe

NH 2-5 CH N CN

OMe

NH 2-6 N CH CN

(C═O)NH₂

NH 2-7 CH N CN

OMe

NH 2-8 CH N OH

CN

O 2-9 CH N H

N(Me)₂

O 2-10 CH N CN

OMe

NH 2-11 CH N Me

Cl

NH 2-12 CH N CN

OMe

NH 2-13 CH N CN

OMe

NH 2-14 CH N H

(C═O)NH₂

O 2-15 N CH Cl

OEt

NH

Also provided herein, in certain embodiments, are compounds of FormulaIII:

-   -   wherein:    -   R¹³ is H, halo, hydroxy, cyano, substituted or unsubstituted        alkyl, substituted or unsubstituted alkoxy, substituted or        unsubstituted alkylamino, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        cycloalkyl, or substituted or unsubstituted heterocycloalkyl;    -   each R¹⁴ is independently halo, hydroxy, cyano, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted alkylamino, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted cycloalkyl, or substituted or unsubstituted        heterocycloalkyl;    -   p is 0-5;    -   Q⁹, Q¹⁰, Q¹¹, Q¹² are independently N or C—R¹⁵; wherein R¹⁵ is        H, halo, hydroxy, cyano,        -   substituted or unsubstituted alkyl or substituted or            unsubstituted alkoxy; provided that at least one of Q⁹, Q¹⁰,            Q¹¹, Q¹² is C—R¹⁵.    -   Y is O, N—R¹⁶ or C(R¹⁶)₂, wherein each R¹⁶ is independently H,        hydroxy, substituted or unsubstituted alkyl; or two R¹⁶ taken        together are (═O) or (═NR¹⁷); wherein R¹⁷ is H, hydroxy,        substituted or unsubstituted alkyl, or substituted or        unsubstituted alkoxy;    -   provided that when Q¹¹ is N, Q⁹, Q¹⁰, Q¹² are C—H, and Y is NH,        R¹³ is not 2-aminoethylamino;        or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula III, Y is N—R¹⁶. In some embodiments,each of Q⁹, Q¹⁰, Q¹¹, and Q¹² are independently N or CH. In someembodiments, R¹³ is substituted or unsubstituted alkoxy, substituted orunsubstituted alkylamino, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, or substituted or unsubstituted heterocycloalkyl. In someembodiments, R¹³ is substituted or unsubstituted alkoxy, or substitutedor unsubstituted alkylamino, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In some embodiments, R¹³ is substituted orunsubstituted alkylamino or heterocycloalkylamino.

In certain embodiments, each R¹⁴ is independently halo, hydroxy, cyano,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,or substituted or unsubstituted alkylamino. In certain embodiments, Q¹¹is N and Q⁹, Q¹⁰ and Q¹² are CH. In some embodiments, Y is NH. In someembodiments, compounds of Formula III are p21-activated kinaseinhibitors.

In certain embodiments, compounds of Formula III are as described inTable 3.

TABLE 3

Com- pound No. Q⁹ Q¹⁰ Q¹¹ Q¹² Y R¹³ R¹⁴ 3-1 N CH CH CH NH

m,p- di- fluoro 3-2 N CH N CH O

p-Cl 3-3 CH N CH CH NH

3,4,5- tri- meth- oxy 3-4 CH N CH CH NH

m-CF₃ 3-5 CH N CH CH NH

m-CF₃ 3-6 CH N CH CH NH

3,4,5- tri- meth- oxy 3-7 CH N CH CH NH

3,4,5- tri- meth- oxy 3-8 CH N CH CH NH

o-F 3-9 CH N CH CH NH

o-Me 3-10 CH N CH CH NH

3,4,5- tri- meth- oxy 3-11 CH N CH CH NH

o-Cl 3-12 CH N N CH O

m- CH₂OH 3-13 CH N CH CH NH

o-F 3-14 CH N CH CH NH

m-F 3-15 CH N CH CH NH

m-CF₃ 3-16 CH N CH CH NH

m-CF₃ 3-17 CH N CH CH NH

m-CF₃

Also provided herein, in certain embodiments, are compounds of FormulaIIIA or pharmaceutically acceptable salt or N-oxide thereof:

wherein:

-   -   R¹ and R² are each independently H, or substituted or        unsubstituted alkyl;    -   R³ is H, —OH, —OR⁶, —SR⁶, —S(═O)₂R⁷, —CO₂R⁸, —N(R⁸)₂,        substituted or unsubstituted alkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted heterocycloalkyl;    -   R⁶ is H or substituted or unsubstituted alkyl;    -   R⁷ is substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted aryl or        substituted or unsubstituted heteroaryl;    -   each R⁸ is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted alkylaryl, substituted or        unsubstituted alkylheteroaryl, substituted or unsubstituted        alkylcycloalkyl, substituted or unsubstituted alkylheterocyclyl,        or two R⁸ together with the nitrogen to which they are attached        form a substituted or unsubstituted heterocycle;    -   each A is independently N or C—H;    -   ring B is aryl or heteroaryl substituted with R⁵;    -   R⁵ is —N(R⁹)₂,    -   R⁹ is H, substituted or unsubstituted alkyl, substituted or        unsubstituted alkylaryl, substituted or unsubstituted        alkylheteroaryl, substituted or unsubstituted alkylcycloalkyl,        substituted or unsubstituted alkylheterocyclyl, or two R⁹        together with the nitrogen to which they are attached form a        substituted or unsubstituted heterocycle; and    -   p is 1-5.

In some embodiments of Formula IIIA, ring B is an aryl ring. In someembodiments of Formula IIIA, ring B is a heteroaryl ring. In someembodiments of Formula IIIA, R³ is OH, —OR⁶ or —N(R⁸)₂. In someembodiments of Formula IIIA, R³ is —N(R⁸)₂. In some embodiments ofFormula IIIA, R⁴ is H. In some embodiments of Formula IIIA, R⁵ is asubstituted or unsubstituted piperidinyl, pyrrolidinyl or piperazinylring. In some embodiments of Formula IIIA, R⁵ is a substituted orunsubstituted alkylaryl ring. In some embodiments, compounds of FormulaIIIA are p21-activated kinase inhibitors.

Also provided herein, in certain embodiments, are compounds of FormulaIV:

-   -   wherein:        -   R¹⁷, R¹⁸ are independently H, substituted or unsubstituted            alkyl, C(═O)—N(R²²)₂, S(O)_(q)—N(R²²)₂, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, substituted            or unsubstituted cycloalkyl, or substituted or unsubstituted            heterocycloalkyl; wherein each R²² is independently H,            substituted or unsubstituted alkyl; substituted or            unsubstituted cycloalkyl, or substituted or unsubstituted            alkylcycloalkyl; and q is 1-2; or R¹⁷ and R¹⁸ together with            the nitrogen to which they are attached from a heterocycle;        -   R¹⁹ is substituted or unsubstituted alkyl, substituted or            unsubstituted alkoxy, substituted or unsubstituted            alkylamino, substituted or unsubstituted heteroalkyl,            substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            cycloalkyl, or substituted or unsubstituted            heterocycloalkyl;        -   R²⁰, R²¹ is H, substituted or unsubstituted alkyl or            substituted or unsubstituted alkylcycloalkyl;        -   L¹, L² are independently O, S(O)_(t), N—R²³ or C(R²³)₂,            wherein each R²³ is independently H, hydroxy, substituted or            unsubstituted alkyl; or two R²³ taken together are (═O) or            (═NR²⁴); R²⁴ is H, hydroxy, substituted or unsubstituted            alkyl, or substituted or unsubstituted alkoxy; t is 1-2;        -   Q¹³ is O, N—R²⁵ or C—R²⁶; wherein R²⁵ is H or substituted or            unsubstituted alkyl; R²⁶ is H, halo, substituted or            unsubstituted alkyl or substituted or unsubstituted alkoxy;        -   Q¹⁴ is N, O, S, or CR²⁶;        -   provided that when R²⁰ is H, R²¹ is methyl, Q¹⁴ is C—CH₃,            L¹, and L² are C═O, and R¹⁷ and R¹⁸ together with the            nitrogen to which they are attached form a heterocycle, R¹⁹            is not (-methylbenzylamino;            or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula IV, L¹ and L² are each independently C═O.In some embodiments, Q¹³ is NH or O. In some embodiments, Q¹⁴ is C—R²⁶.In some embodiments, R¹⁷ and R¹⁸ are each independently H or substitutedor unsubstituted alkyl. In some embodiments, R¹⁷ and R¹⁸ together withthe nitrogen to which they are attached form a heterocycle. In someembodiments, R¹⁹ is substituted or unsubstituted alkyl, substituted orunsubstituted alkylamino, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl. In some embodiments, R¹⁹ is substituted or unsubstitutedalkylaryl or substituted or unsubstituted alkylheteroaryl.

In some embodiments, R²⁰ is H. In some embodiments, R²¹ is substitutedor unsubstituted alkyl. In some embodiments, L¹ is C═O. In someembodiments, L² is C═O. In some embodiments, L¹ and L² are C═O. In someembodiments, compounds of Formula IV are p21-activated kinaseinhibitors.

In certain embodiments, compounds of Formula IV are as described inTable 4.

TABLE 4

Compound No. Q¹³ R¹⁹ R²⁰ R²¹ L² NR¹⁷R¹⁸ 4-1 NH

H H C═O

4-2 NMe

H Me C═O

4-3 O

Me Me C═O

4-4 NH

H H SO₂

4-5 NH

Me Me SO₂

4-6 NH

H Me C═O

4-7 NH

H Me C═O

Provided herein, in some embodiments, are compounds having the structureof Formula V or pharmaceutically acceptable salt or N-oxide thereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, or halogen;    -   R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰,        N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   Q is substituted or unsubstituted cycloalkyl or heterocycloalkyl        fused to ring A;    -   ring A is substituted or unsubstituted aryl or heteroaryl        substituted with 0-4 R⁴;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkoxy, substituted or unsubstituted            heteroalkyl, substituted or unsubstituted cycloalkyl or            substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8;        provided that when Q is unsubstituted indane,        tetrahydronaphthalene or fluorene, and R⁶ is H, ring B is not        unsubstituted phenyl and R⁵ is not para substituted piperidinyl,        pyrazolyl or methylpiperazinyl.

In some embodiments, the compound of Formula V has the structure ofFormula VI:

-   -   wherein:    -   each of Y³, Y⁴ and Y⁵ are independently a bond, O, N—R^(1a),        CR¹R², SO₂, or C═O;    -   R^(1a)is H or substituted or unsubstituted alkyl;    -   R¹ and R² are each independently H, halogen, —CN, —NO₂, —OH,        —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,        —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰,        —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted        alkyl, substituted or unsubstituted alkoxy, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl or substituted or unsubstituted heterocycloalkyl;    -   s is 0-4.

In some embodiments, the compound of Formula V has the structure ofFormula VII:

-   -   wherein:    -   ring A is an aryl or heteroaryl substituted with R⁴;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl;            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroary, or two R¹⁰                together with the nitrogen to which they are attached                form a heterocycle;        -   each R¹¹ is independently hydrogen, halogen, —CN, —NO₂, —OH,            —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl; or two R¹¹ together with the carbon atom            to which they are attached form C═O;    -   s is 0-4;    -   k is 1-4;    -   z is 0 or 1;    -   u is 1, 2 or 3;    -   provided that z+u≠1;    -   ring B is an aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8;    -   R⁶ is H, or halogen;    -   R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰,        N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl.

In some embodiments of Formula V, VI or VII, ring A is heteroaryl ringcomprising 1-3 nitrogen atoms, an oxygen atom, a sulfur atom, or anycombination thereof. In some embodiments of Formula V, VI or VII, ring Ais a phenyl ring.

In some embodiments, a compound of Formula VII has a structure ofFormula VIIA, Formula VIIB, Formula VIIC, Formula VIID, Formula VIIE,Formula VIIF, Formula VIIG or Formula VIIH:

In some embodiments of Formula VII, R¹¹ is H, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy or N(R¹⁰)₂. Insome embodiments of Formula VII, R¹¹ is H. In some embodiments ofFormula VII, each R⁴ is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl. In some embodiments of Formula VII, each R⁴ isindependently Cl, F, CF₃ or OMe.

In some embodiments, compounds of Formula V are as described in theExample section and Table 5:

TABLE 5

Com- pound No. B Q R⁶ R⁷ R⁵ 5-1 

H OH

5-2 

H Me

5-3 

H H

5-4 

Cl H

5-5 

H H

5-6 

H H

5-7 

H CONH₂

5-8 

H

5-9 

Cl

5-10

H H

5-11

H Cl

5-12

Me H

5-13

H OMe

5-14

H H

15-15 

H CN

5-16

H H

5-17

H isopropyl

5-18

Cl H p-SO₂Me 5-20

F

5-21

H

5-22

H

5-23

H H

5-24

H H

Provided herein, in some embodiments, are compounds having the structureof Formula VA or pharmaceutically acceptable salt or N-oxide thereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, or halogen;    -   R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰,        N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or substituted or unsubstituted heteroaryl;    -   Q is substituted or unsubstituted cycloalkyl or heterocycloalkyl        fused to ring A;    -   ring A is substituted or unsubstituted aryl or heteroaryl        substituted with 0-4 R⁴;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂,            substituted or unsubstituted alkyl, substituted or            unsubstituted alkoxy, substituted or unsubstituted            heteroalkyl, substituted or unsubstituted cycloalkyl or            substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8.

Provided herein, in some embodiments, are compounds having the structureof Formula VIII or pharmaceutically acceptable salt or N-oxide thereof:

-   -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkoxy,        —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted aryl        or substituted or unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl, or R¹ and R² together        with the carbon to which they are attached form a C₃-C₆        cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R⁴;    -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H,        —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,        —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,        —NR¹⁰C(═O)R¹⁰, —N R¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted        or unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl;        -   R⁸ is H or substituted or unsubstituted alkyl;        -   R⁹ is substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted aryl            or substituted or unsubstituted heteroaryl        -   each R¹⁰ is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl, or two R¹⁰ together with the atoms to which they            are attached form a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8;    -   provided that when s is zero, then R² is not methyl.

In some embodiments of Formula VIII, R¹ is H or C₁-C₅ alkyl. In someembodiments of Formula VIII, R² is C₁-C₅ alkyl. In some embodiments ofFormula VIII, R² is C₂-C₅ alkyl. In some embodiments of Formula VIII, R²is ethyl, propyl or isopropyl.

In some embodiments of Formula VIII,

-   -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkoxy,        —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted aryl        or substituted or unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl, or R¹ and R² together        with the carbon to which they are attached form a C₃-C₆        cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R³ and R⁴;        -   R³ is halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,            —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,            —NR¹⁰C(═O)R⁹, NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted            or unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃,            —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,            —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,            —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,            —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,            substituted or unsubstituted alkoxy, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            cycloalkyl or substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹⁰                together with the atoms to which they are attached form                a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8.

In some embodiments, a compound of Formula VIII has the structure ofFormula VIIIA or Formula VIIIB:

In some embodiments, the compound of Formula VIII has the structure ofFormula (IX):

wherein:

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl; and    -   R³ is halogen, alkyl, fluoroalkyl, alkoxy, fluoroalkoxy, SR⁸,        —S(═O)R⁹, or —S(═O)₂R⁹, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl.

In some embodiments of Formula VIII, R³ is F, Cl, SCF₃, CF₃, OMe, (R) or(S) —S(═O)R⁹ or —S(O)₂R⁹.

In some embodiments, the compound of Formula IX has the structure ofFormula (IXA) or Formula (IXB):

In some embodiments of Formula IX, R¹ is H or C₁-C₅ alkyl. In someembodiments of Formula IX, R² is C₁-C₅ alkyl. In some embodiments ofFormula IX, R² is C₂-C₅ alkyl. In some embodiments of Formula IX, R² isethyl, propyl or isopropyl.

In some embodiments, compounds of Formula VIII, VIIIA, VIIIB, IX, IXAand/or IXB are as described in the Examples section and in Table 6.

TABLE 6

Com- pound No. B

R⁶ R⁷ R⁵ 6-1

H OH

6-2

H Me

6-3

H H

6-4

Cl H

6-5

H H

6-6

H H

6-7

H CONH₂

6-8

H

6-9

Cl

6-10

H H

6-11

H Cl

6-12

Me H

6-13

H OMe

6-14

H H

6-15

H CN

6-16

H H

6-17

H isopropyl

6-18

Cl H p-SO₂Me 6-20

F

6-21

H

6-22

H

6-23

H H

6-24

H H

Provided herein, in some embodiments, are compounds having the structureof Formula VIIIC or pharmaceutically acceptable salt or N-oxide thereof:

-   -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkoxy,        —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted cycloalkyl, substituted or unsubstituted aryl        or substituted or unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ is H or substituted or unsubstituted alkyl;    -   R² is substituted or unsubstituted alkyl, or R¹ and R² together        with the carbon to which they are attached form a C₃-C₆        cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R⁴;    -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H,        —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,        —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,        —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl;        -   R⁸ is H or substituted or unsubstituted alkyl;        -   R⁹ is substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted aryl            or substituted or unsubstituted heteroaryl        -   each R¹⁰ is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl, or two R¹⁰ together with the atoms to which they            are attached form a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;

r is 0-8.

Also provided herein, in some embodiments, are compound having thestructure of Formula X or pharmaceutically acceptable salt or N-oxidethereof:

-   -   wherein:    -   W is a bond;    -   R⁶ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —N(R¹⁰)₂, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted aryl or substituted or        unsubstituted heteroaryl;    -   R⁷ is H, halogen, —CN, —OH, substituted or unsubstituted alkyl,        substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰,        —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl or substituted or unsubstituted heteroaryl;    -   Q is

-   -   R¹ and R² are each independently H or substituted or        unsubstituted alkyl; or R¹ and R² together with the carbon to        which they are attached form a C₃-C₆ cycloalkyl ring;    -   p is 1, 2 or 3;    -   ring A is aryl substituted with R³ and R⁴;    -   R³ is a substituted or unsubstituted heteroaryl, substituted or        unsubstituted cycloalkyl or substituted or unsubstituted        heterocycloalkyl attached to ring A via a carbon atom;        -   each R⁴ is independently halogen, —CN, —NO₂, —OH, —OCF₃,            —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,            —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,            —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,            —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,            substituted or unsubstituted alkoxy, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            cycloalkyl or substituted or unsubstituted heterocycloalkyl;            -   R⁸ is H or substituted or unsubstituted alkyl;            -   R⁹ is substituted or unsubstituted alkyl, substituted or                unsubstituted cycloalkyl, substituted or unsubstituted                aryl or substituted or unsubstituted heteroaryl            -   each R¹⁰ is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl or                substituted or unsubstituted heteroaryl, or two R¹³                together with the atoms to which they are attached form                a heterocycle;    -   s is 0-4;    -   ring B is aryl or heteroaryl substituted with R⁵;        -   each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,            —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,            —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,            —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted cycloalkyl or substituted or unsubstituted            heterocycloalkyl;    -   r is 0-8.

In some embodiments of Formula X, R³ is located at the ortho position onring A, relative to the position of the group

In some embodiments of Formula X, R³ is located at the meta position onring A, relative to the position of the group

In some embodiments of Formula X, R³ is located at the para position onring A, relative to the position of the group

In some embodiments of Formula X, Q is:

In some embodiments of Formula X, Q is

In some embodiments of Formula X, R³ is a C₃-C₆ cycloalkyl ring, a5-6-membered heteroaryl ring comprising 1-3 nitrogen atoms, an oxygenatom, a sulfur atom, or any combination thereof, or a 3-6-memberedheterocycloalkyl ring comprising 1-3 nitrogen atoms, an oxygen atom, asulfur atom, or any combination thereof, that is attached to ring via acarbon atom and wherein R³ is further substituted by halogen, cyano,alkyl, alkoxy, —SR⁸, (R) or (S)—S(O)R⁹ or —S(O)₂R⁹.

In some embodiments of Formula X, R¹ and R² are H. In some embodimentsof Formula X, one of R¹ and R² is H, and the other of R¹ and R² is C₁-C₅alkyl.

In some embodiments, compounds of Formula X are as described in theExamples section and Table 7.

TABLE 7

Compound No. B

R⁶ R⁷ R⁵ 7-1

H OH

7-2

H Me

7-3

H H

7-4

Cl H

7-5

H H

7-6

H H

7-7

H CONH₂

7-8

H

7-9

Cl

7-10

H H

7-11

H Cl

7-12

Me H

7-13

H OMe

7-14

H H

7-15

H CN

7-16

H H

7-17

H isopropyl

7-18

Cl H p-SO₂Me 7-20

F

7-21

H

7-22

H

7-23

H H

7-24

H H

In some embodiments, a PAK inhibitor is a small molecule. As referred toherein, a “small molecule” is an organic molecule that is less thanabout 5 kilodaltons (kDa) in size. In some embodiments, the smallmolecule is less than about 4 kDa, 3 kDa, about 2 kDa, or about 1 kDa.In some embodiments, the small molecule is less than about 800 daltons(Da), about 600 Da, about 500 Da, about 400 Da, about 300 Da, about 200Da, or about 100 Da. In some embodiments, a small molecule is less thanabout 4000 g/mol, less than about 3000 g/mol, 2000 g/mol, less thanabout 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol,or less than about 500 g/mol. In some embodiments, small molecules arenon-polymeric. Typically, small molecules are not proteins,polypeptides, polynucleotides, oligonucleotides, polysaccharides,glycoproteins, or proteoglycans, but includes peptides of up to about 40amino acids. A derivative of a small molecule refers to a molecule thatshares the same structural core as the original small molecule, butwhich is prepared by a series of chemical reactions from the originalsmall molecule. As one example, a pro-drug of a small molecule is aderivative of that small molecule. An analog of a small molecule refersto a molecule that shares the same or similar structural core as theoriginal small molecule, and which is synthesized by a similar orrelated route, or art-recognized variation, as the original smallmolecule.

In certain embodiments, compounds described herein have one or morechiral centers. As such, all stereoisomers are envisioned herein. Invarious embodiments, compounds described herein are present in opticallyactive or racemic forms. It is to be understood that the compoundsdescribed herein encompass racemic, optically-active, regioisomeric andstereoisomeric forms, or combinations thereof that possess thetherapeutically useful properties described herein. Preparation ofoptically active forms is achieve in any suitable manner, including byway of non-limiting example, by resolution of the racemic form byrecrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase. In some embodiments,mixtures of one or more isomer is utilized as the therapeutic compounddescribed herein. In certain embodiments, compounds described hereincontains one or more chiral centers. These compounds are prepared by anymeans, including enantioselective synthesis and/or separation of amixture of enantiomers and/or diastereomers. Resolution of compounds andisomers thereof is achieved by any means including, by way ofnon-limiting example, chemical processes, enzymatic processes,fractional crystallization, distillation, chromatography, and the like.

In various embodiments, pharmaceutically acceptable salts describedherein include, by way of non-limiting example, a nitrate, chloride,bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate,gluconate, benzoate, propionate, butyrate, sulfosalicylate, maleate,laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate,p-toluenenesulfonate, mesylate and the like. Furthermore,pharmaceutically acceptable salts include, by way of non-limitingexample, alkaline earth metal salts (e.g., calcium or magnesium), alkalimetal salts (e.g., sodium-dependent or potassium), ammonium salts andthe like.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O,¹⁷O, ¹⁸O, ³²P, ³⁵S or the like. In some embodiments,isotopically-labeled compounds are useful in drug and/or substratetissue distribution studies. In some embodiments, substitution withheavier isotopes such as deuterium affords certain therapeuticadvantages resulting from greater metabolic stability (for example,increased in vivo half-life or reduced dosage requirements). In someembodiments, substitution with positron emitting isotopes, such as ¹¹C,¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds are prepared by any suitable method or by processes using anappropriate isotopically-labeled reagent in place of the non-labeledreagent otherwise employed.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as described herein aremodified by the use of appropriate reagents and conditions, for theintroduction of the various moieties found in the formula as providedherein. As a guide the following synthetic methods are utilized.

Compounds described herein are synthesized using any suitable proceduresstarting from compounds that are available from commercial sources, orare prepared using procedures described herein.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein are modified using various electrophilesand/or nucleophiles to form new functional groups or substituents. TableA entitled “Examples of Covalent Linkages and Precursors Thereof” listsselected non-limiting examples of covalent linkages and precursorfunctional groups which yield the covalent linkages. Table A is used asguidance toward the variety of electrophiles and nucleophilescombinations available that provide covalent linakges. Precursorfunctional groups are shown as electrophilic groups and nucleophilicgroups.

TABLE A Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

In the reactions described, it is necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In some embodiments it is contemplated that each protectivegroup be removable by a different means. Protective groups that arecleaved under totally disparate reaction conditions fulfill therequirement of differential removal.

In some embodiments, protective groups are removed by acid, base,reducing conditions (such as, for example, hydrogenolysis), and/oroxidative conditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and are used to protect carboxy andhydroxy reactive moieties in the presence of amino groups protected withCbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties areblocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

In some embodiments carboxylic acid and hydroxy reactive moieties areblocked with hydrolytically removable protective groups such as thebenzyl group, while amine groups capable of hydrogen bonding with acidsare blocked with base labile groups such as Fmoc. Carboxylic acidreactive moieties are protected by conversion to simple ester compoundsas exemplified herein, which include conversion to alkyl esters, or areblocked with oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups are blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and are subsequentlyremoved by metal or pi-acid catalysts. For example, an allyl-blockedcarboxylic acid is deprotected with a Pd⁰-catalyzed reaction in thepresence of acid labile t-butyl carbamate or base-labile acetate amineprotecting groups. Yet another form of protecting group is a resin towhich a compound or intermediate is attached. As long as the residue isattached to the resin, that functional group is blocked and does notreact. Once released from the resin, the functional group is availableto react.

Typically blocking/protecting groups are selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

Certain Definitions

As used herein the term “Treatment” or “treating” includes achieving atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderor condition being treated. For example, in an individual with aneuropsychiatric condition, therapeutic benefit includes partial orcomplete halting of the progression of the disorder, or partial orcomplete reversal of the disorder. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological or psychological symptoms associated with the underlyingcondition such that an improvement is observed in the patient,notwithstanding the fact that the patient is still affected by thecondition. A prophylactic benefit of treatment includes prevention of acondition, retarding the progress of a condition, or decreasing thelikelihood of occurrence of a condition. As used herein, “treating” or“treatment” includes prophylaxis.

As used herein, the phrase “neuropsychiatric condition” refers to anycondition that results in chronic impairment in cognition, affect,and/or motor function. Neuropsychiatiric conditions include and are notlimited to schizophrenia, Alzheimer's disease, mild cognitiveimpairment, age-related cognitive decline, Parkinson's disease, FragileX Syndrome, autism spectrum disorder, clinical depression, epilepsy,Huntington's disease, mental retardation, Down's syndrome, Niemann-Pickdisease, spongiform encephalitis, Lafora disease, Maple syrup urinedisease, maternal phenylketonuria, cognitive decline associated withmenopause, Rett's syndrome, atypical phenylketonuria, or tuberoussclerosis or the like.

As used herein, the phrase “abnormal spine size” refers to dendriticspine volumes or dendritic spine surface areas (e.g., volumes or surfaceareas of the spine heads and/or spine necks) associated with aneuropsychiatric condition that deviate significantly relative to spinevolumes or surface areas in the same brain region (e.g., the CA1 region,the prefrontal cortex) in a normal individual (e.g., a mouse, rat, orhuman) of the same age; such abnormalities are determined asappropriate, including, e.g., tissue samples, relevant animal models,post-mortem analyses, or other model systems.

The phrase “defective spine morphology” or “abnormal spine morphology”or “aberrant spine morphology” refers to abnormal dendritic spineshapes, volumes, surface areas, length, width (e.g., diameter of theneck), spine density, spine head diameter, spine head volume, spine headsurface area, ratio of mature to immature spines, ratio of spine volumeto spine length, ratio of spine head diameter to spine length, or thelike that is associated with a neuropsychiatric condition relative tothe dendritic spine shapes, volumes, surface areas, length, width (e.g.,diameter of the neck), spine density, spine head diameter, spine headvolume, spine head surface area, ratio of mature to immature spines,ratio of spine volume to spine length, ratio of spine head diameter tospine length, or the like observed in the same brain region in a normalindividual (e.g., a mouse, rat, or human) of the same age; suchabnormalities or defects are determined as appropriate, including, e.g.,tissue samples, relevant animal models, post-mortem analyses, or othermodel systems.

The phrase “abnormal spine function” or “defective spine function” or“aberrant spine function” refers to a defect of dendritic spines toundergo stimulus-dependent morphological or functional changes (e.g.,calcium entry through NMDA receptors, activation of AMPA receptors, LTP,LTD, etc) associated with a neuropsychiatric condition as compared todendritic spines in the same brain region in a normal individual of thesame age. The “defect” in spine function includes, e.g., a reduction indendritic spine plasticity, (e.g., an abnormally small change indendritic spine morphology or actin re-arrangement in the dendriticspine), or an excess level of dendritic plasticity, (e.g., an abnormallylarge change in dendritic spine morphology or actin re-arrangement inthe dendritic spine). Such abnormalities or defects are determined asappropriate, including, e.g., tissue samples, relevant animal models,post-mortem analyses, or other model systems.

The phrase “abnormal spine motility” refers to a significant low or highmovement of dendritic spines associated with a neuropsychiatriccondition as compared to dendritic spines in the same brain region in anormal individual of the same age. Any defect in spine morphology (e.g.,spine length, density or the like) or synaptic plasticity or synapticfunction (e.g., LTP, LTD or the like) occurs in any region of the brain,including, for example, the frontal cortex, the hippocampus, theamygdala, the CA I region, the prefrontal cortex or the like. Suchabnormalities or defects are determined as appropriate, including, e.g.,tissue samples, relevant animal models, post-mortem analyses, or othermodel systems.

As used herein, the phrase “biologically active” refers to acharacteristic of any substance that has activity in a biological systemand/or organism. For instance, a substance that, when administered to anorganism, has a biological effect on that organism, is considered to bebiologically active. In particular embodiments, where a protein orpolypeptide is biologically active, a portion of that protein orpolypeptide that shares at least one biological activity of the proteinor polypeptide is typically referred to as a “biologically active”portion.

As used herein, the term “effective amount” is an amount, which whenadministered systemically, is sufficient to effect beneficial or desiredresults, such as beneficial or desired clinical results, or enhancedcognition, memory, mood, or other desired effects. An effective amountis also an amount that produces a prophylactic effect, e.g., an amountthat delays, reduces, or eliminates the appearance of a pathological orundesired condition associated with a neuropsychiatric condition. Aneffective amount is optionally administered in one or moreadministrations. In terms of treatment, an “effective amount” of acomposition described herein is an amount that is sufficient topalliate, ameliorate, stabilize, reverse or slow the progression of aneuropsychiatric condition, e.g., cognitive decline. An “effectiveamount” includes any PAK inhibitor used alone or in conjunction with oneor more agents used to treat a disease or disorder. An “effectiveamount” of a therapeutic agent as described herein will be determined bya patient's attending physician or other medical care provider. Factorswhich influence what a therapeutically effective amount will be include,the absorption profile (e.g., its rate of uptake into the brain) of thePAK inhibitor, time elapsed since the initiation of disease, and theage, physical condition, existence of other disease states, andnutritional status of an individual being treated. Additionally, othermedication the patient is receiving, e.g., antipsychotic drugs used incombination with a PAK inhibitor, will typically affect thedetermination of the therapeutically effective amount of the therapeuticagent to be administered.

As used herein, the term “inhibitor” refers to a molecule which iscapable of inhibiting (including partially inhibiting or allostericinhibition) one or more of the biological activities of a targetmolecule, e.g., a p21-activated kinase. Inhibitors, for example, act byreducing or suppressing the activity of a target molecule and/orreducing or suppressing signal transduction. In some embodiments, a PAKinhibitor described herein causes substantially complete inhibition ofone or more PAKs. In some embodiments, the phrase “partial inhibitor”refers to a molecule which can induce a partial response for example, bypartially reducing or suppressing the activity of a target moleculeand/or partially reducing or suppressing signal transduction. In someinstances, a partial inhibitor mimics the spatial arrangement,electronic properties, or some other physicochemical and/or biologicalproperty of the inhibitor. In some instances, in the presence ofelevated levels of an inhibitor, a partial inhibitor competes with theinhibitor for occupancy of the target molecule and provides a reductionin efficacy, relative to the inhibitor alone. In some embodiments, a PAKinhibitor described herein is a partial inhibitor of one or more PAKs.In some embodiments, a PAK inhibitor described herein is an allostericmodulator of PAK. In some embodiments, a PAK inhibitor described hereinblocks the p21 binding domain of PAK. In some embodiments, a PAKinhibitor described herein blocks the ATP binding site of PAK. In someembodiments, a PAK inhibitor is a “Type II” kinase inhibitor. In someembodiment a PAK inhibitor stabilizes PAK in its inactive conformation.In some embodiments, a PAK inhibitor stabilizes the “DFG-out”conformation of PAK.

In some embodiments, PAK inhibitors reduce, abolish, and/or remove thebinding between PAK and at least one of its natural binding partners(e.g., Cdc42 or Rac). In some instances, binding between PAK and atleast one of its natural binding partners is stronger in the absence ofa PAK inhibitor (by e.g., 90%, 80%, 70%, 60%, 50%, 40%, 30% or 20%) thanin the presence of a PAK inhibitor. Alternatively or additionally, PAKinhibitors inhibit the phosphotransferase activity of PAK, e.g., bybinding directly to the catalytic site or by altering the conformationof PAK such that the catalytic site becomes inaccessible to substrates.In some embodiments, PAK inhibitors inhibit the ability of PAK tophosphorylate at least one of its target substrates, e.g., LIM kinase 1(LIMK1), myosin light chain kinase (MLCK), cortactin; or itself. PAKinhibitors include inorganic and/or organic compounds.

In some embodiments, PAK inhibitors described herein increase dendriticspine length. In some embodiments, PAK inhibitors described hereindecrease dendritic spine length. In some embodiments, PAK inhibitorsdescribed herein increase dendritic neck diameter. In some embodiments,PAK inhibitors described herein decrease dendritic neck diameter. Insome embodiments, PAK inhibitors described herein increase dendriticspine head diameter. In some embodiments, PAK inhibitors describedherein decrease dendritic spine head diameter. In some embodiments, PAKinhibitors described herein increase dendritic spine head volume. Insome embodiments, PAK inhibitors described herein decrease dendriticspine head volume. In some embodiments, PAK inhibitors described hereinincrease dendritic spine surface area. In some embodiments, PAKinhibitors described herein decrease dendritic spine surface area. Insome embodiments, PAK inhibitors described herein increase dendriticspine density. In some embodiments, PAK inhibitors described hereindecrease dendritic spine density. In some embodiments, PAK inhibitorsdescribed herein increase the number of mushroom shaped spines. In someembodiments, PAK inhibitors described herein decrease the number ofmushroom shaped spines.

In some embodiments, a PAK inhibitor suitable for the methods describedherein is a direct PAK inhibitor. In some embodiments, a PAK inhibitorsuitable for the methods described herein is an indirect PAK inhibitor.In some embodiments, a PAK inhibitor suitable for the methods describedherein decreases PAK activity relative to a basal level of PAK activityby about 1.1 fold to about 100 fold, e.g., to about 1.2 fold, 1.5 fold,1.6 fold, 1.7 fold, 2.0 fold, 3.0 fold, 5.0 fold, 6.0 fold, 7.0 fold,8.5 fold, 9.7 fold, 10 fold, 12 fold, 14 fold, 15 fold, 20 fold, 30fold, 40 fold, 50 fold, 60 fold, 70 fold, 90 fold, 95 fold, or by anyother amount from about 1.1 fold to about 100 fold relative to basal PAKactivity. In some embodiments, the PAK inhibitor is a reversible PAKinhibitor. In other embodiments, the PAK inhibitor is an irreversiblePAK inhibitor. Direct PAK inhibitors are optionally used for themanufacture of a medicament for treating a neuropsychiatric condition.

In some embodiments, a PAK inhibitor used for the methods describedherein has in vitro ED₅₀ for PAK activation of less than 100 μM (e.g.,less than 10 μM, less than 5 μM, less than 4 μM, less than 3 μM, lessthan 1 μM, less than 0.8 μM, less than 0.6 μM, less than 0.5 μM, lessthan 0.4 μM, less than 0.3 μM, less than less than 0.2 μM, less than 0.1μM, less than 0.08 μM, less than 0.06 μM, less than 0.05 μM, less than0.04 μM, less than 0.03 μM, less than less than 0.02 μM, less than 0.01μM, less than 0.0099 μM, less than 0.0098 μM, less than 0.0097 μM, lessthan 0.0096 μM, less than 0.0095 μM, less than 0.0094 μM, less than0.0093 μM, less than 0.00092 μM, or less than 0.0090 μM).

In some embodiments, a PAK inhibitor used for the methods describedherein has in vitro ED₅₀ for PAK activation of less than 100 μM (e.g.,less than 10 μM, less than 5 μM, less than 4 μM, less than 3 μM, lessthan 1 μM, less than 0.8 μM, less than 0.6 μM, less than 0.5 μM, lessthan 0.4 μM, less than 0.3 μM, less than less than 0.2 μM, less than 0.1μM, less than 0.08 μM, less than 0.06 μM, less than 0.05 μM, less than0.04 μM, less than 0.03 μM, less than less than 0.02 μM, less than 0.01μM, less than 0.0099 μM, less than 0.0098 μM, less than 0.0097 μM, lessthan 0.0096 μM, less than 0.0095 μM, less than 0.0094 μM, less than0.0093 μM, less than 0.00092 μM, or less than 0.0090 μM).

As used herein, synaptic function refers to synaptic transmission and/orsynaptic plasticity, including stabilization of synaptic plasticity. Asused herein, “defect in synaptic plasticity” or “aberrant synapticplasticity” refers to abnormal synaptic plasticity following stimulationof that synapse. In some embodiments, a defect in synaptic plasticity isa decrease in LTP. In some embodiments, a defect in synaptic plasticityis an increase in LTD. In some embodiments, a defect in synapticplasticity is erratic (e.g., fluctuating, randomly increasing ordecreasing) synaptic plasticity. In some instances, measures of synapticplasticity are LTP and/or LTD (induced, for example, by theta-burststimulation, high-frequency stimulation for LTP, low-frequency (e.g.,e.g., 1 Hz) stimulation for LTD) and LTP and/or LTD after stabilization.In some embodiments, stabilization of LTP and/or LTD occurs in anyregion of the brain including the frontal cortex, the hippocampus, theprefrontal cortex, the amygdala or any combination thereof.

As used herein “stabilization of synaptic plasticity” refers to stableLTP or LTD following induction (e.g., by theta-burst stimulation,high-frequency stimulation for LTP, low-frequency (e.g., e.g., 1 Hz)stimulation for LTD).

“Aberrant stabilization of synaptic transmission” (for example, aberrantstabilization of LTP or LTD), refers to failure to establish a stablebaseline of synaptic transmission following an induction paradigm (e.g.,by theta-burst stimulation, high-frequency stimulation for LTP,low-frequency (e.g., 1 Hz) stimulation for LTD) or an extended period ofvulnerability to disruption by pharmacological or electrophysiologicalmeans

As used herein “synaptic transmission” or “baseline synaptictransmission” refers to the EPSP and/or IPSP amplitude and frequency,neuronal excitability or population spike thresholds of a normalindividual (e.g., an individual not suffering from a neuropsychiatriccondition) or that predicted for an animal model for a normalindividual. As used herein “aberrant synaptic transmission” or“defective synaptic transmission” refers to any deviation in synaptictransmission compared to synaptic transmission of a normal individual orthat predicted for an animal model for a normal individual. In someembodiments, an individual suffering from a neuropsychiatric conditionhas a defect in baseline synaptic transmission that is a decrease inbaseline synaptic transmission compared to the baseline synaptictransmission in a normal individual or that predicted for an animalmodel for a normal individual. In some embodiments, an individualsuffering from a neuropsychiatric condition has a defect in baselinesynaptic transmission that is an increase in baseline synaptictransmission compared to the baseline synaptic transmission in a normalindividual or that predicted for an animal model for a normalindividual.

As used herein “sensorimotor gating” is assessed, for example, bymeasuring prepulse inhibition (PPI) and/or habituation of the humanstartle response. In some embodiments, a defect in sensorimotor gatingis a deficit in sensorimotor gating. In some embodiments, a defect insensorimotor gating is an enhancement of sensorimotor gating.

As used herein, “normalization of aberrant synaptic plasticity” refersto a change in aberrant synaptic plasticity in an individual sufferingfrom, suspected of having, or pre-disposed to a neuropsychiatriccondition to a level of synaptic plasticity that is substantially thesame as the synaptic plasticity of a normal individual or to thatpredicted from an animal model for a normal individual. As used herein,substantially the same means, for example, about 90% to about 110% ofthe measured synaptic plasticity in a normal individual or to thatpredicted from an animal model for a normal individual. In otherembodiments, substantially the same means, for example, about 80% toabout 120% of the measured synaptic plasticity in a normal individual orto that predicted from an animal model for a normal individual. In yetother embodiments, substantially the same means, for example, about 70%to about 130% of the synaptic plasticity in a normal individual or tothat predicted from an animal model for a normal individual. As usedherein, “partial normalization of aberrant synaptic plasticity” refersto any change in aberrant synaptic plasticity in an individual sufferingfrom, suspected of having, or pre-disposed to a neuropsychiatriccondition that trends towards synaptic plasticity of a normal individualor to that predicted from an animal model for a normal individual. Asused herein “partially normalized synaptic plasticity” or “partiallynormal synaptic plasticity” is, for example, ±about 25%, ±about 35%,±about 45%, ±about 55%, ±about 65%, or ±about 75% of the synapticplasticity of a normal individual or to that predicted from an animalmodel for a normal individual. In some embodiments, normalization orpartial normalization of aberrant synaptic plasticity in an individualsuffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is lowering of aberrant synaptic plasticitywhere the aberrant synaptic plasticity is higher than the synapticplasticity of a normal individual or to that predicted from an animalmodel for a normal individual. In some embodiments, normalization orpartial normalization of aberrant synaptic plasticity in an individualsuffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is an increase in aberrant synapticplasticity where the aberrant synaptic plasticity is lower than thesynaptic plasticity of a normal individual or to that predicted from ananimal model for a normal individual. In some embodiments, normalizationor partial normalization of synaptic plasticity in an individualsuffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is a change from an erratic (e.g.,fluctuating, randomly increasing or decreasing) synaptic plasticity to anormal (e.g. stable) or partially normal (e.g., less fluctuating)synaptic plasticity compared to the synaptic plasticity of a normalindividual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof synaptic plasticity in an individual suffering from, suspected ofhaving, or pre-disposed to a neuropsychiatric condition is a change froma non-stabilizing synaptic plasticity to a normal (e.g., stable) orpartially normal (e.g., partially stable) synaptic plasticity comparedto the synaptic plasticity of a normal individual or to that predictedfrom an animal model for a normal individual.

As used herein, “normalization of aberrant baseline synaptictransmission” refers to a change in aberrant baseline synaptictransmission in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition to a level of baselinesynaptic transmission that is substantially the same as the baselinesynaptic transmission of a normal individual or to that predicted froman animal model for a normal individual. As used herein, substantiallythe same means, for example, about 90% to about 110% of the measuredbaseline synaptic transmission in a normal individual or to thatpredicted from an animal model for a normal individual. In otherembodiments, substantially the same means, for example, about 80% toabout 120% of the measured baseline synaptic transmission in a normalindividual or to that predicted from an animal model for a normalindividual. In yet other embodiments, substantially the same means, forexample, about 70% to about 130% of the measured baseline synaptictransmission in a normal individual or to that predicted from an animalmodel for a normal individual. As used herein, “partial normalization ofaberrant baseline synaptic transmission” refers to any change inaberrant baseline synaptic transmission in an individual suffering from,suspected of having, or pre-disposed to a neuropsychiatric conditionthat trends towards baseline synaptic transmission of a normalindividual or to that predicted from an animal model for a normalindividual. As used herein “partially normalized baseline synaptictransmission” or “partially normal baseline synaptic transmission” is,for example, ±about 25%, ±about 35%, ±about 45%, ±about 55%, ±about 65%,or ±about 75% of the measured baseline synaptic transmission of a normalindividual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof aberrant baseline synaptic transmission in an individual sufferingfrom, suspected of having, or pre-disposed to a neuropsychiatriccondition is lowering of aberrant baseline synaptic transmission wherethe aberrant baseline synaptic transmission is higher than the baselinesynaptic transmission of a normal individual or to that predicted froman animal model for a normal individual. In some embodiments,normalization or partial normalization of aberrant baseline synaptictransmission in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition is an increase in aberrantbaseline synaptic transmission where the aberrant baseline synaptictransmission is lower than the baseline synaptic transmission of anormal individual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof baseline synaptic transmission in an individual suffering from,suspected of having, or pre-disposed to a neuropsychiatric condition isa change from an erratic (e.g., fluctuating, randomly increasing ordecreasing) baseline synaptic transmission to a normal (e.g. stable) orpartially normal (e.g., less fluctuating) baseline synaptic transmissioncompared to the baseline synaptic transmission of a normal individual orto that predicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of aberrant baselinesynaptic transmission in an individual suffering from, suspected ofhaving, or pre-disposed to a neuropsychiatric condition is a change froma non-stabilizing baseline synaptic transmission to a normal (e.g.,stable) or partially normal (e.g., partially stable) baseline synaptictransmission compared to the baseline synaptic transmission of a normalindividual or to that predicted from an animal model for a normalindividual.

As used herein, “normalization of aberrant synaptic function” refers toa change in aberrant synaptic function in an individual suffering from,suspected of having, or pre-disposed to a neuropsychiatric condition toa level of synaptic function that is substantially the same as thesynaptic function of a normal individual or to that predicted from ananimal model for a normal individual. As used herein, substantially thesame means, for example, about 90% to about 110% of the synapticfunction in a normal individual or to that predicted from an animalmodel for a normal individual. In other embodiments, substantially thesame means, for example, about 80% to about 120% of the synapticfunction in a normal individual or to that predicted from an animalmodel for a normal individual. In yet other embodiments, substantiallythe same means, for example, about 70% to about 130% of the synapticfunction in a normal individual or to that predicted from an animalmodel for a normal individual. As used herein, “partial normalization ofaberrant synaptic function” refers to any change in aberrant synapticfunction in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition that trends towardssynaptic function of a normal individual or to that predicted from ananimal model for a normal individual. As used herein “partiallynormalized synaptic function” or “partially normal synaptic function”is, for example, ±about 25%, ±about 35%, ±about 45%, ±about 55%, ±about65%, or ±about 75% of the measured synaptic function of a normalindividual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof aberrant synaptic function in an individual suffering from, suspectedof having, or pre-disposed to a neuropsychiatric condition is loweringof aberrant synaptic function where the aberrant synaptic function ishigher than the synaptic function of a normal individual or to thatpredicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of aberrant synapticfunction in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition is an increase in aberrantsynaptic function where the aberrant synaptic function is lower than thesynaptic function of a normal individual or to that predicted from ananimal model for a normal individual. In some embodiments, normalizationor partial normalization of synaptic function in an individual sufferingfrom, suspected of having, or pre-disposed to a neuropsychiatriccondition is a change from an erratic (e.g., fluctuating, randomlyincreasing or decreasing) synaptic function to a normal (e.g. stable) orpartially normal (e.g., less fluctuating) synaptic function compared tothe synaptic function of a normal individual or to that predicted froman animal model for a normal individual. In some embodiments,normalization or partial normalization of aberrant synaptic function inan individual suffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is a change from a non-stabilizing synapticfunction to a normal (e.g., stable) or partially normal (e.g., partiallystable) synaptic function compared to the synaptic function of a normalindividual or to that predicted from an animal model for a normalindividual.

As used herein, “normalization of aberrant long term potentiation (LTP)”refers to a change in aberrant LTP in an individual suffering from,suspected of having, or pre-disposed to a neuropsychiatric condition toa level of LTP that is substantially the same as the LTP of a normalindividual or to that predicted from an animal model for a normalindividual. As used herein, substantially the same means, for example,about 90% to about 110% of the LTP in a normal individual or to thatpredicted from an animal model for a normal individual. In otherembodiments, substantially the same means, for example, about 80% toabout 120% of the LTP in a normal individual or to that predicted froman animal model for a normal individual. In yet other embodiments,substantially the same means, for example, about 70% to about 130% ofthe LTP in a normal individual or to that predicted from an animal modelfor a normal individual. As used herein, “partial normalization ofaberrant LTP” refers to any change in aberrant LTP in an individualsuffering from, suspected of having, or pre-disposed to aneuropsychiatric condition that trends towards LTP of a normalindividual or to that predicted from an animal model for a normalindividual. As used herein “partially normalized LTP” or “partiallynormal LTP” is, for example, ±about 25%, ±about 35%, ±about 45%, ±about55%, ±about 65%, or ±about 75% of the measured LTP of a normalindividual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof aberrant LTP in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition is lowering of aberrant LTPwhere the aberrant LTP is higher than the LTP of a normal individual orto that predicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of aberrant LTP inan individual suffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is an increase in aberrant LTP where theaberrant LTP is lower than the LTP of a normal individual or to thatpredicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of LTP in anindividual suffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is a change from an erratic (e.g.,fluctuating, randomly increasing or decreasing) LTP to a normal (e.g.stable) or partially normal (e.g., less fluctuating) LTP compared to theLTP of a normal individual or to that predicted from an animal model fora normal individual. In some embodiments, normalization or partialnormalization of aberrant LTP in an individual suffering from, suspectedof having, or pre-disposed to a neuropsychiatric condition is a changefrom a non-stabilizing LTP to a normal (e.g., stable) or partiallynormal (e.g., partially stable) LTP compared to the LTP of a normalindividual or to that predicted from an animal model for a normalindividual.

As used herein, “normalization of aberrant long term depression (LTD)”refers to a change in aberrant LTD in an individual suffering from,suspected of having, or pre-disposed to a neuropsychiatric condition toa level of LTD that is substantially the same as the LTD of a normalindividual or to that predicted from an animal model for a normalindividual. As used herein, substantially the same means, for example,about 90% to about 110% of the LTD in a normal individual or to thatpredicted from an animal model for a normal individual. In otherembodiments, substantially the same means, for example, about 80% toabout 120% of the LTD in a normal individual or to that predicted froman animal model for a normal individual. In yet other embodiments,substantially the same means, for example, about 70% to about 130% ofthe LTD in a normal individual or to that predicted from an animal modelfor a normal individual. As used herein, “partial normalization ofaberrant LTD” refers to any change in aberrant LTD in an individualsuffering from, suspected of having, or pre-disposed to aneuropsychiatric condition that trends towards LTD of a normalindividual or to that predicted from an animal model for a normalindividual. As used herein “partially normalized LTD” or “partiallynormal LTD” is, for example, ±about 25%, ±about 35%, ±about 45%, ±about55%, ±about 65%, or ±about 75% of the measured LTD of a normalindividual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof aberrant LTD in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition is lowering of aberrant LTDwhere the aberrant LTD is higher than the LTD of a normal individual orto that predicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of aberrant LTD inan individual suffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is an increase in aberrant LTD where theaberrant LTD is lower than the LTD of a normal individual or to thatpredicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of LTD in anindividual suffering from, suspected of having, or pre-disposed to aneuropsychiatric condition is a change from an erratic (e.g.,fluctuating, randomly increasing or decreasing) LTD to a normal (e.g.stable) or partially normal (e.g., less fluctuating) LTD compared to theLTD of a normal individual or to that predicted from an animal model fora normal individual. In some embodiments, normalization or partialnormalization of aberrant LTD in an individual suffering from, suspectedof having, or pre-disposed to a neuropsychiatric condition is a changefrom a non-stabilizing LTD to a normal (e.g., stable) or partiallynormal (e.g., partially stable) LTD compared to the LTD of a normalindividual or to that predicted from an animal model for a normalindividual.

As used herein, “normalization of aberrant sensorimotor gating” refersto a change in aberrant sensorimotor gating in an individual sufferingfrom, suspected of having, or pre-disposed to a neuropsychiatriccondition to a level of sensorimotor gating that is substantially thesame as the sensorimotor gating of a normal individual or to thatpredicted from an animal model for a normal individual. As used herein,substantially the same means, for example, about 90% to about 110% ofthe sensorimotor gating in a normal individual or to that predicted froman animal model for a normal individual. In other embodiments,substantially the same means, for example, about 80% to about 120% ofthe sensorimotor gating in a normal individual or to that predicted froman animal model for a normal individual. In yet other embodiments,substantially the same means, for example, about 70% to about 130% ofthe sensorimotor gating in a normal individual or to that predicted froman animal model for a normal individual. As used herein, “partialnormalization of aberrant sensorimotor gating” refers to any change inaberrant sensorimotor gating in an individual suffering from, suspectedof having, or pre-disposed to a neuropsychiatric condition that trendstowards sensorimotor gating of a normal individual or to that predictedfrom an animal model for a normal individual. As used herein “partiallynormalized sensorimotor gating” or “partially normal sensorimotorgating” is, for example, ±about 25%, ±about 35%, ±about 45%, ±about 55%,±about 65%, or ±about 75% of the measured sensorimotor gating of anormal individual or to that predicted from an animal model for a normalindividual. In some embodiments, normalization or partial normalizationof aberrant sensorimotor gating in an individual suffering from,suspected of having, or pre-disposed to a neuropsychiatric condition islowering of aberrant sensorimotor gating where the aberrant sensorimotorgating is higher than the sensorimotor gating of a normal individual orto that predicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of aberrantsensorimotor gating in an individual suffering from, suspected ofhaving, or pre-disposed to a neuropsychiatric condition is an increasein aberrant sensorimotor gating where the aberrant sensorimotor gatingis lower than the sensorimotor gating of a normal individual or to thatpredicted from an animal model for a normal individual. In someembodiments, normalization or partial normalization of sensorimotorgating in an individual suffering from, suspected of having, orpre-disposed to a neuropsychiatric condition is a change from an erratic(e.g., fluctuating, randomly increasing or decreasing) sensorimotorgating to a normal (e.g. stable) or partially normal (e.g., lessfluctuating) sensorimotor gating compared to the sensorimotor gating ofa normal individual or to that predicted from an animal model for anormal individual. In some embodiments, normalization or partialnormalization of aberrant sensorimotor gating in an individual sufferingfrom, suspected of having, or pre-disposed to a neuropsychiatriccondition is a change from a non-stabilizing sensorimotor gating to anormal (e.g., stable) or partially normal (e.g., partially stable)sensorimotor gating compared to the sensorimotor gating of a normalindividual or to that predicted from an animal model for a normalindividual.

As used herein, “expression” of a nucleic acid sequence refers to one ormore of the following events: (1) production of an RNA template from aDNA sequence (e.g., by transcription); (2) processing of an RNAtranscript (e.g., by splicing, editing, 5′ cap formation, and/or 3′ endformation); (3) translation of an RNA into a polypeptide or protein; (4)post-translational modification of a polypeptide or protein.

As used herein the term “PAK polypeptide” or “PAK protein” or “PAK”refers to a protein that belongs in the family of p21-activatedserine/threonine protein kinases. These include mammalian isoforms ofPAK, e.g., the Group I PAK proteins (sometimes referred to as Group APAK proteins), including PAK1, PAK2, PAK3, as well as the Group II PAKproteins (sometimes referred to as Group B PAK proteins), includingPAK4, PAK5, and/or PAK6 Also included as PAK polypeptides or PAKproteins are lower eukaryotic isoforms, such as the yeast Step 20(Leberter et al., 1992, EMBO J., 11:4805; incorporated herein byreference) and/or the Dictyostelium single-headed myosin I heavy chainkinases (Wu et al., 1996, J. Biol. Chem., 271:31787; incorporated hereinby reference). Representative examples of PAK amino acid sequencesinclude, but are not limited to, human PAK1 (GenBank Accession NumberAAA65441), human PAK2 (GenBank Accession Number AAA65442), human PAK3(GenBank Accession Number AAC36097), human PAK 4 (GenBank AccessionNumbers NP_(—)005875 and CAA09820), human PAK5 (GenBank AccessionNumbers CAC18720 and BAA94194), human PAK6 (GenBank Accession NumbersNP_(—)064553 and AAF82800), human PAK1 (GenBank Accession NumberQ9P286), C. elegans PAK (GenBank Accession Number BAA 11844), D.melanogaster PAK (GenBank Accession Number AAC47094), and rat PAK1(GenBank Accession Number AAB95646). In some embodiments, a PAKpolypeptide comprises an amino acid sequence that is at least 70% to100% identical, e.g., at least 75%, 80%, 85%, 86%, 87%, 88%, 90%, 91%,92%, 94%, 95%, 96%, 97%, 98%, or any other percent from about 70% toabout 100% identical to sequences of GenBank Accession Numbers AAA65441,AAA65442, AAC36097, NP_(—)005875, CAA09820, CAC18720, BAA94194,NP_(—)064553, AAF82800, Q9P286, BAA 11844, AAC47094, and/or AAB95646. Insome embodiments, a Group I PAK polypeptide comprises an amino acidsequence that is at least 70% to 100% identical, e.g., at least 75%,80%, 85%, 86%, 87%, 88%, 90%, 91%, 92%, 94%, 95%, 96%, 97%, 98%, or anyother percent from about 70% to about 100% identical to sequences ofGenBank Accession Numbers AAA65441, AAA65442, and/or AAC36097.

Representative examples of PAK genes encoding PAK proteins include, butare not limited to, human PAK1 (GenBank Accession Number U24152), humanPAK2 (GenBank Accession Number U24153), human PAK3 (GenBank AccessionNumber AF068864), human PAK4 (GenBank Accession Number AJ011855), humanPAK5, (GenBank Accession Number AB040812), and human PAK6 (GenBankAccession Number AF276893). In some embodiments, a PAK gene comprises anucleotide sequence that is at least 70% to 100% identical, e.g., atleast 75%, 80%, 85%, 86%, 87%, 88%, 90%, 91%, 92%, 94%, 95%, 96%, 97%,98%, or any other percent from about 70% to about 100% identical tosequences of GenBank Accession Numbers U24152, U24153, AF068864,AJ011855, AB040812, and/or AF276893. In some embodiments, a Group I PAKgene comprises a nucleotide sequence that is at least 70% to 100%identical, e.g., at least 75%, 80%, 85%, 86%, 87%, 88%, 90%, 91%, 92%,94%, 95%, 96%, 97%, 98%, or any other percent from about 70% to about100% identical to sequences of GenBank Accession Numbers U24152, U24153,and/or AF068864.

To determine the percent homology of two amino acid sequences or of twonucleic acids, the sequences are aligned for optimal comparison purposes(e.g., gaps can be introduced in the sequence of a first amino acid ornucleic acid sequence for optimal alignment with a second amino ornucleic acid sequence). The amino acid residues or nucleotides atcorresponding amino acid positions or nucleotide positions are thencompared. When a position in the first sequence is occupied by the sameamino acid residue or nucleotide as the corresponding position in thesecond sequence, then the molecules are identical at that position. Thepercent homology between the two sequences is a function of the numberof identical positions shared by the sequences (i.e., % identity=# ofidentical positions/total # of positions (e.g., overlappingpositions)×100). In one embodiment the two sequences are the samelength.

To determine percent homology between two sequences, the algorithm ofKarlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268,modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA90:5873-5877 is used. Such an algorithm is incorporated into the NBLASTand XBLAST programs of Altschul, et al. (1990) J. Mol. Biol.215:403-410. BLAST nucleotide searches are performed with the NBLASTprogram, score=100, wordlength=12 to obtain nucleotide sequenceshomologous to a nucleic acid molecules described or disclose herein.BLAST protein searches are performed with the XBLAST program, score=50,wordlength=3. To obtain gapped alignments for comparison purposes,Gapped BLAST is utilized as described in Altschul et al. (1997) NucleicAcids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs,the default parameters of the respective programs (e.g., XBLAST andNBLAST) are used. See the website of the National Center forBiotechnology Information for further details (on the world wide web atncbi.nlm.nih.gov). Proteins suitable for use in the methods describedherein also includes proteins having between 1 to 15 amino acid changes,e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acidsubstitutions, deletions, or additions, compared to the amino acidsequence of any protein PAK inhibitor described herein. In otherembodiments, the altered amino acid sequence is at least 75% identical,e.g., 77%, 80%, 82%, 85%, 88%, 90%, 92%, 95%, 97%, 98%, 99%, or 100%identical to the amino acid sequence of any protein PAK inhibitordescribed herein. Such sequence-variant proteins are suitable for themethods described herein as long as the altered amino acid sequenceretains sufficient biological activity to be functional in thecompositions and methods described herein. Where amino acidsubstitutions are made, the substitutions should be conservative aminoacid substitutions. Among the common amino acids, for example, a“conservative amino acid substitution” is illustrated by a substitutionamong amino acids within each of the following groups: (1) glycine,alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine,and tryptophan, (3) serine and threonine, (4) aspartate and glutamate,(5) glutamine and asparagine, and (6) lysine, arginine and histidine.The BLOSUM62 table is an amino acid substitution matrix derived fromabout 2,000 local multiple alignments of protein sequence segments,representing highly conserved regions of more than 500 groups of relatedproteins (Henikoff et al (1992), Proc. Natl. Acad. Sci. USA,89:10915-10919). Accordingly, the BLOSUM62 substitution frequencies areused to define conservative amino acid substitutions that may beintroduced into the amino acid sequences described or described herein.Although it is possible to design amino acid substitutions based solelyupon chemical properties (as discussed above), the language“conservative amino acid substitution” preferably refers to asubstitution represented by a BLOSUM62 value of greater than −1. Forexample, an amino acid substitution is conservative if the substitutionis characterized by a BLOSUM62 value of 0, 1, 2, or 3. According to thissystem, preferred conservative amino acid substitutions arecharacterized by a BLOSUM62 value of at least 1 (e.g., 1, 2 or 3), whilemore preferred conservative amino acid substitutions are characterizedby a BLOSUM62 value of at least 2 (e.g., 2 or 3).

As used herein, the term “PAK activity,” unless otherwise specified,includes, but is not limited to, at least one of PAK protein-proteininteractions, PAK phosphotransferase activity (intermolecular orintermolecular), translocation, etc of one or more PAK isoforms.

As used herein, a “PAK inhibitor” refers to any molecule, compound, orcomposition that directly or indirectly decreases the PAK activity. Insome embodiments, PAK inhibitors inhibit, decrease, and/or abolish thelevel of a PAK mRNA and/or protein or the half-life of PAK mRNA and/orprotein, such inhibitors are referred to as “clearance agents”. In someembodiments, a PAK inhibitor is a PAK antagonist that inhibits,decreases, and/or abolishes an activity of PAK. In some embodiments, aPAK inhibitor also disrupts, inhibits, or abolishes the interactionbetween PAK and its natural binding partners (e.g., a substrate for aPAK kinase, a Rac protein, a cdc42 protein, LIM kinase) or a proteinthat is a binding partner of PAK in a pathological condition, asmeasured using standard methods. In some embodiments, the PAK inhibitoris a Group I PAK inhibitor that inhibits, for example, one or more GroupI PAK polypeptides, for example, PAK1, PAK2, and/or PAK3. In someembodiments, the PAK inhibitor is a PAK1 inhibitor. In some embodiments,the PAK inhibitor is a PAK2 inhibitor. In some embodiments, the PAKinhibitor is a PAK3 inhibitor. In some embodiments, the PAK inhibitor isa mixed PAK1/PAK3 inhibitor. In some embodiments, the PAK inhibitorinhibits all three Group I PAK isoforms (PAK1,2 and PAK3) with equal orsimilar potency. In some embodiments, the PAK inhibitor is a Group IIPAK inhibitor that inhibits one or more Group II PAK polypeptides, forexample PAK4, PAK5, and/or PAK6. In some embodiments, the PAK inhibitoris a PAK4 inhibitor. In some embodiments, the PAK inhibitor is a PAK5inhibitor. In some embodiments, the PAK inhibitor is a PAK6 inhibitor.In some embodiments, the PAK inhibitor is a PAK7 inhibitor. As usedherein, a PAK5 polypeptide is substantially homologous to a PAK7polypeptide.

In some embodiments, PAK inhibitors reduce, abolish, and/or remove thebinding between PAK and at least one of its natural binding partners(e.g., Cdc42 or Rac). In some instances, binding between PAK and atleast one of its natural binding partners is stronger in the absence ofa PAK inhibitor (by e.g., 90%, 80%, 70%, 60%, 50%, 40%, 30% or 20%) thanin the presence of a PAK inhibitor. In some embodiments, PAK inhibitorsprevent, reduce, or abolish binding between PAK and a protein thatabnormally accumulates or aggregates in cells or tissue in a diseasestate. In some instances, binding between PAK and at least one of theproteins that aggregates or accumulates in a cell or tissue is strongerin the absence of a PAK inhibitor (by e.g., 90%, 80%, 70%, 60%, 50%,40%, 30% or 20%) than in the presence of an inhibitor.

A “individual” or an “individual,” as used herein, is a mammal. In someembodiments, an individual is an animal, for example, a rat, a mouse, adog or a monkey. In some embodiments, an individual is a human patient.In some embodiments a “individual” or an “individual” is a human. Insome embodiments, an individual suffers from a neuropsychiatriccondition or is suspected to be suffering from a neuropsychiatriccondition or is pre-disposed to a neuropsychiatric condition.

In some embodiments, a pharmacological composition comprising a PAKinhibitor is “administered peripherally” or “peripherally administered.”As used herein, these terms refer to any form of administration of anagent, e.g., a therapeutic agent, to an individual that is not directadministration to the CNS, i.e., that brings the agent in contact withthe non-brain side of the blood-brain barrier. “Peripheraladministration,” as used herein, includes intravenous, intra-arterial,subcutaneous, intramuscular, intraperitoneal, transdermal, byinhalation, transbuccal, intranasal, rectal, oral, parenteral,sublingual, or trans-nasal. In some embodiments, a PAK inhibitor isadministered by an intracerebral route.

The terms “polypeptide,” and “protein” are used interchangeably hereinto refer to a polymer of amino acid residues. That is, a descriptiondirected to a polypeptide applies equally to a description of a protein,and vice versa. The terms apply to naturally occurring amino acidpolymers as well as amino acid polymers in which one or more amino acidresidues is a non-naturally occurring amino acid, e.g., an amino acidanalog. As used herein, the terms encompass amino acid chains of anylength, including full length proteins (i.e., antigens), wherein theamino acid residues are linked by covalent peptide bonds.

The term “amino acid” refers to naturally occurring and non-naturallyoccurring amino acids, as well as amino acid analogs and amino acidmimetics that function in a manner similar to the naturally occurringamino acids. Naturally encoded amino acids are the 20 common amino acids(alanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine, and valine) and pyrolysine and selenocysteine. Amino acidanalogs refers to compounds that have the same basic chemical structureas a naturally occurring amino acid, i.e., an a carbon that is bound toa hydrogen, a carboxyl group, an amino group, and an R group, such as,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (such as, norleucine) ormodified peptide backbones, but retain the same basic chemical structureas a naturally occurring amino acid.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise,may be referred to by their commonly to accepted single-letter codes.

The term “nucleic acid” refers to deoxyribonucleotides,deoxyribonucleosides, ribonucleosides, or ribonucleotides and polymersthereof in either single- or double-stranded form. Unless specificallylimited, the term encompasses nucleic acids containing known analoguesof natural nucleotides which have similar binding properties as thereference nucleic acid and are metabolized in a manner similar tonaturally occurring nucleotides. Unless specifically limited otherwise,the term also refers to oligonucleotide analogs including PNA(peptidonucleic acid), analogs of DNA used in antisense technology(phosphorothioates, phosphoroamidates, and the like). Unless otherwiseindicated, a particular nucleic acid sequence also implicitlyencompasses conservatively modified variants thereof (including but notlimited to, degenerate codon substitutions) and complementary sequencesas well as the sequence explicitly indicated. Specifically, degeneratecodon substitutions may be achieved by generating sequences in which thethird position of one or more selected (or all) codons is substitutedwith mixed-base and/or deoxyinosine residues (Batzer et al., NucleicAcid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608(1985); and Cassol et al. (1992); Rossolini et al., Mol. Cell. Probes8:91-98 (1994)).

The terms “isolated” and “purified” refer to a material that issubstantially or essentially removed from or concentrated in its naturalenvironment. For example, an isolated nucleic acid is one that isseparated from the nucleic acids that normally flank it or other nucleicacids or components (proteins, lipids, etc.) in a sample. In anotherexample, a polypeptide is purified if it is substantially removed fromor concentrated in its natural environment. Methods for purification andisolation of nucleic acids and proteins are documented methodologies.

The term “antibody” describes an immunoglobulin whether natural orpartly or wholly synthetically produced. The term also covers anypolypeptide or protein having a binding domain which is, or ishomologous to, an antigen-binding domain. CDR grafted antibodies arealso contemplated by this term.

The term antibody as used herein will also be understood to mean one ormore fragments of an antibody that retain the ability to specificallybind to an antigen, (see generally, Holliger et al., Nature Biotech. 23(9) 1126-1129 (2005)). Non-limiting examples of such antibodies include(i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CLand CH1 domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprisingtwo Fab fragments linked by a disulfide bridge at the hinge region;(iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fvfragment consisting of the VL and VH domains of a single arm of anantibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544 546),which consists of a VH domain; and (vi) an isolated complementaritydetermining region (CDR). Furthermore, although the two domains of theFv fragment, VL and VH, are coded for by separate genes, they areoptionally joined, using recombinant methods, by a synthetic linker thatenables them to be made as a single protein chain in which the VL and VHregions pair to form monovalent molecules (known as single chain Fv(scFv); see e.g., Bird et al. (1988) Science 242:423 426; and Huston etal. (1988) Proc. Natl. Acad. Sci. USA 85:5879 5883; and Osbourn et al.(1998) Nat. Biotechnol. 16:778). Such single chain antibodies are alsointended to be encompassed within the term antibody. Any VH and VLsequences of specific scFv is optionally linked to human immunoglobulinconstant region cDNA or genomic sequences, in order to generateexpression vectors encoding complete IgG molecules or other isotypes. VHand VL are also optionally used in the generation of Fab, Fv or otherfragments of immunoglobulins using either protein chemistry orrecombinant DNA technology. Other forms of single chain antibodies, suchas diabodies are also encompassed.

“F(ab′)2” and “Fab” moieties are optionally produced by treatingimmunoglobulin (monoclonal antibody) with a protease such as pepsin andpapain, and includes an antibody fragment generated by digestingimmunoglobulin near the disulfide bonds existing between the hingeregions in each of the two H chains. For example, papain cleaves IgGupstream of the disulfide bonds existing between the hinge regions ineach of the two H chains to generate two homologous antibody fragmentsin which an L chain composed of VL (L chain variable region) and CL (Lchain constant region), and an H chain fragment composed of VH (H chainvariable region) and CHγ1 (γ1 region in the constant region of H chain)are connected at their C terminal regions through a disulfide bond. Eachof these two homologous antibody fragments is called Fab′. Pepsin alsocleaves IgG downstream of the disulfide bonds existing between the hingeregions in each of the two H chains to generate an antibody fragmentslightly larger than the fragment in which the two above-mentioned Fab′are connected at the hinge region. This antibody fragment is calledF(ab′)2.

The Fab fragment also contains the constant domain of the light chainand the first constant domain (CH1) of the heavy chain. Fab′ fragmentsdiffer from Fab fragments by the addition of a few residues at thecarboxyl terminus of the heavy chain CH1 domain including one or morecysteine(s) from the antibody hinge region. Fab′-SH is the designationherein for Fab′ in which the cysteine residue(s) of the constant domainsbear a free thiol group. F(ab′)2 antibody fragments originally wereproduced as pairs of Fab′ fragments which have hinge cysteines betweenthem. Other chemical couplings of antibody fragments are documented.

“Fv” is the minimum antibody fragment which contains a completeantigen-recognition and antigen-binding site. This region consists of adimer of one heavy chain and one light chain variable domain in tight,non-covalent association. It is in this configuration that the threehypervariable regions of each variable domain interact to define anantigen-binding site on the surface of the VH-VL dimer. Collectively,the six hypervariable regions confer antigen-binding specificity to theantibody. However, even a single variable domain (or half of an Fvcomprising only three hypervariable regions specific for an antigen) hasthe ability to recognize and bind antigen, although at a lower affinitythan the entire binding site.

“Single-chain Fv” or “sFv” antibody fragments comprise a VH, a VL, orboth a VH and VL domain of an antibody, wherein both domains are presentin a single polypeptide chain. In some embodiments, the Fv polypeptidefurther comprises a polypeptide linker between the VH and VL domainswhich enables the sFv to form the desired structure for antigen binding.For a review of sFv see, e.g., Pluckthun in The-Pharmacology ofMonoclonal Antibodies, Vol. 113, Rosenburg and Moore eds.Springer-Verlag, New York, pp. 269 315 (1994).

A “chimeric” antibody includes an antibody derived from a combination ofdifferent mammals. The mammal is, for example, a rabbit, a mouse, a rat,a goat, or a human. The combination of different mammals includescombinations of fragments from human and mouse sources.

In some embodiments, an antibody described or described herein is amonoclonal antibody (MAb), typically a chimeric human-mouse antibodyderived by humanization of a mouse monoclonal antibody. Such antibodiesare obtained from, e.g., transgenic mice that have been “engineered” toproduce specific human antibodies in response to antigenic challenge. Inthis technique, elements of the human heavy and light chain locus areintroduced into strains of mice derived from embryonic stem cell linesthat contain targeted disruptions of the endogenous heavy chain andlight chain loci. In some embodiments, the transgenic mice synthesizehuman antibodies specific for human antigens, and the mice are used toproduce human antibody-secreting hybridomas.

The term “optionally substituted” or “substituted” means that thereferenced group substituted with one or more additional group(s). Incertain embodiments, the one or more additional group(s) areindividually and independently selected from amide, ester, alkyl,cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,ester, alkylsulfone, arylsulfone, cyano, halogen, alkoyl, alkoyloxo,isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy,fluoroalkyl, amino, alkyl-amino, dialkyl-amino, amido, carbonyl,sulfonyl, or the like.

As used herein, where a subsituent is attached to a ring “via a carbonatom,” the bond between the substituent and the ring is a carbon-carbonbond.

An “alkyl” group refers to an aliphatic hydrocarbon group. An “alkyl”group includes substituted and unsubstituted alkyl groups. Reference toan alkyl group includes “saturated alkyl” and/or “unsaturated alkyl”.The alkyl group, whether saturated or unsaturated, includes branched,straight chain, or cyclic groups. By way of example only, alkyl includesmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,t-butyl, pentyl, iso-pentyl, neo-pentyl, and hexyl. In some embodiments,alkyl groups include, but are in no way limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl,ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. A “lower alkyl” is a C₁-C₆ alkyl. A“heteroalkyl” group substitutes any one of the carbons of the alkylgroup with a heteroatom having the appropriate number of hydrogen atomsattached (e.g., a CH₂ group to an NH group or an O group).

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, whereinalkyl is as defined herein and x and y are selected from the group x=1,y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with thenitrogen to which they are attached, optionally form a cyclic ringsystem.

An “amide” is a chemical moiety with formula C(O)NHR or NHC(O)R, where Ris selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through aring carbon) and heteroalicyclic (bonded through a ring carbon).

The term “ester” refers to a chemical moiety with formula —C(═O)OR,where R is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl and heteroalicyclic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. An “aryl” group includessubstituted and unsubstituted aryl groups. Aryl rings described hereininclude rings having five, six, seven, eight, nine, or more than ninecarbon atoms. Aryl groups are optionally substituted. Examples of arylgroups include, but are not limited to phenyl, and naphthalenyl.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. A “cycloalkyl” group includes substituted andunsubstituted cycloalkyl groups. In various embodiments, cycloalkyls aresaturated, or partially unsaturated. In some embodiments, cycloalkylsare fused with an aromatic ring. In some embodiments, cycloalkyls arefused with a heteroaryl ring. Cycloalkyl groups include groups havingfrom 3 to 10 ring atoms. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, the following moieties:

and the like. Monocyclic cycloalkyls include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Dicylclic cycloalkyls include, but are not limited totetrahydronaphthyl, indanyl, tetrahydropentalene or the like. Polycycliccycloalkyls include admantane, norbornane or the like. The termcycloalkyl includes “unsaturated nonaromatic carbocyclyl” or“nonaromatic unsaturated carbocyclyl” both of which refer to anonaromatic carbocyclyle, as defined herein, that contains at least onecarbon carbon double bond or one carbon carbon triple bond.

The term “heterocycle” refers to heteroaromatic and heteroalicyclicgroups containing one to four ring heteroatoms each selected from O, Sand N. In certain instances, each heterocyclic group has from 4 to 10atoms in its ring system, and with the proviso that the ring of saidgroup does not contain two adjacent O or S atoms. Non-aromaticheterocyclic groups include groups having 3 atoms in their ring system,but aromatic heterocyclic groups must have at least 5 atoms in theirring system. The heterocyclic groups include benzo-fused ring systems.An example of a 3-membered heterocyclic group is aziridinyl (derivedfrom aziridine). An example of a 4-membered heterocyclic group isazetidinyl (derived from azetidine). An example of a 5-memberedheterocyclic group is thiazolyl. An example of a 6-membered heterocyclicgroup is pyridyl, and an example of a 10-membered heterocyclic group isquinolinyl. Examples of non-aromatic heterocyclic groups arepyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groupsare pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. A “heteroaryl” group includes substitutedand unsubstituted heteroaryl groups. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. In certainembodiments, heteroaryl groups are monocyclic or polycyclic.Illustrative examples of heteroaryl groups include the followingmoieties:

and the like.

A “heteroalicyclic” group or “heterocyclo” group or “heterocycloalkyl”group refers to a cycloalkyl group, wherein at least one skeletal ringatom is a heteroatom selected from nitrogen, oxygen and sulfur. A“heterocycloalkyl” group includes substituted and unsubstitutedheterocycloalkyl groups. In various embodiments, the radicals are fusedwith an aryl or heteroaryl. Illustrative examples of heterocyclo groups,also referred to as non-aromatic heterocycles, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The terms “haloalkyl,” and “haloalkoxy” include alkyl and alkoxystructures that are substituted with one or more halogens. Inembodiments, where more than one halogen is included in the group, thehalogens are the same or they are different. The terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

The term “heteroalkyl” include optionally substituted alkyl, alkenyl andalkynyl radicals which have one or more skeletal chain atoms selectedfrom an atom other than carbon, e.g., oxygen, nitrogen, sulfur,phosphorus, silicon, or combinations thereof. In certain embodiments,the heteroatom(s) is placed at any interior position of the heteroalkylgroup. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —C₁₋₁₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In some embodiments, up to two heteroatoms areconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

A “cyano” group refers to a CN group.

An “isocyanato” group refers to a NCO group.

A “thiocyanato” group refers to a CNS group.

An “isothiocyanato” group refers to a NCS group.

“Alkoyloxy” refers to a RC(═O)O— group.

“Alkoyl” refers to a RC(═O)— group.

Synthesis of Compounds

In some embodiments, compounds of Formula V are synthesized according toprocedures described in Scheme 1 and in the Examples section.

A reaction of an appropriate amine with ethyl4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1) furnishes a compound(2) as shown in Scheme 1. Reduction of the ester to an alcohol followedby oxidation of the alcohol to an aldehyde furnishes the intermediate(4). A Horner-Wadsworth Emmons reaction furnishes compound (5) which iscyclized in the presence of DBU to provide intermediate (6). Oxidationof the thiomethyl moiety in the presence of oxone furnishes a mixture ofthe sulfone and sulfoxide intermediates (7) and (8). Reaction of thesulfonyl compound with an amine (9) furnishes compounds of Formula V.

Amines Q-NH₂ that are compatible with the procedures described hereininclude and are not limited to

In some embodiments, amines Q-NH₂ are synthesized according toprocedures described in Scheme 2 and in the Examples section. Boranereduction of oxime (11) furnishes amine (12). In some embodiments,spiroborate-catalyzed borane reduction of an oxime (11) provides achiral amine (13).

In some embodiments, compounds of Formulae VIII are synthesizedaccording to procedures described in Scheme 3 and in the Examplessection.

A reaction of ammonia with ethyl4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1) furnishes compound(14) as shown in Scheme 2. The ester moiety in compound 14 is reduced toan alcohol and oxidized to an aldehylde to yield compound 16. A HornerWadsworth Emmons reaction furnishes compound 17 which is then cyclizedin the presence of DBU to furnish compound 18. Compound 18 is alkylatedwith an appropriate benzyl halide, such as, for example, compound 20 inthe presence of a strong base such as, for example, sodium hydride toyield compound 19. The thiomethyl group is oxidized in the presence ofoxone and the methyl sulfone group in compound 20 is subjected to adisplacement reaction with an appropriate amine 9 to yield compound 21.Other benzyl halides are compatible with the procedure described inScheme 2 include and are not limited to

As shown in Scheme 4 below, the bromide group in compound 19 isoptionally subjected to further reactions such as, for example, a Suzukireaction with an appropriate boronic acid to yield compounds of FormulaX.

Examples of boronic acids that are compatible with the proceduresdescribed in Scheme 4 include and are not limited to

In some embodiments, amines (9) that are compatible with the proceduresdescribed herein include and are not limited to

where X is F, Cl, CF₃, CHF₂, SO₂Me, or the like.

In some embodiments, compounds of Formula IIIA are synthesized accordingto procedures described in Scheme 5 and in the Examples section.

Reaction of dimethylacetamide with an appropriate ketone 26 providesintermediate 27. Reaction of an aniline 24 with cyanamide provides theguanidine 25. reaction of the guanidine 25 with intermediate 27 providescompounds of structure 28 as shown in Scheme 5. Displacement of thechloride in compound 28 with an appropriate amine 29 furnishes compoundsof Formula IIIA.

Methods

Provided herein are methods for treating neuropsychiatric conditionscomprising administration of a therapeutically effective amount of ap21-activated kinase inhibitor (e.g., a compound of Formula I-X) to anindividual in need thereof. In some embodiments of the methods providedherein, administration of a p21-activated kinase inhibitor alleviates orreverses one or more behavioral symptoms (e.g., social withdrawal,depersonalization, loss of appetite, loss of hygiene, delusions,hallucinations, depression, blunted affect, avolition, anhedonia,alogia, the sense of being controlled by outside forces or the like) ofthe neuropsychiatric condition (e.g. negative symptoms ofschizophrenia). In some embodiments of the methods provided herein,administration of a p21-activated kinase inhibitor (e.g., a compound ofFormula I-X) alleviates or reverses one or more negative symptoms and/orcognition impairment associated with a neuropsychiatric condition (e.g.,impairment in executive function, comprehension, inference,decision-making, planning, learning or memory associated withschizophrenia, Alzheimer's disease, FXS, autism or the like).

Also provided herein are methods for modulation of dendritic spinemorphology and/or synaptic function comprising administering to anindividual in need thereof (e.g., an individual suffering from orsuspected of having schizophrenia, Parkinson's disease, Alzheimer'sdisease, epilepsy or the like) a therapeutically effective amount of aPAK inhibitor (e.g., a compound of Formula I-X). In some embodiments,modulation of dendritic spine morphology and/or synaptic functionalleviates or reverses negative symptoms and/or cognitive impairmentassociated with neuropsychiatric conditions. In some embodiments,modulation of dendritic spine morphology and/or synaptic function haltsor delays further deterioration of neuropsychiatric symptoms (e.g.,progression of cognitive impairments and/or loss of bodily functions).In some embodiments, modulation of dendritic spine morphology and/orsynaptic function stabilizes or reverses symptoms of disease (e.g.,reduces frequency of epileptic seizures, stabilizes mild cognitiveimpairment and prevents progression to early dementia). In someembodiments of the methods provided herein, administration of ap21-activated kinase inhibitor halts or delays progressive loss ofmemory and/or cognition associated with a neuropsychiatric condition(e.g., Alzheimer's disease).

Provided herein are methods for modulation of synaptic function orsynaptic plasticity comprising administering to an individual in needthereof (e.g., an individual suffering from or suspected of having anyneuropsychiatric condition described herein) a therapeutically effectiveamount of a PAK inhibitor (e.g., a compound of Formula I-X). Modulationof synaptic function or plasticity includes, for example, alleviation orreversal of defects in LTP, LTD or the like.

Defects in LTP include, for example, an increase in LTP or a decrease inLTP in any region of the brain in an individual suffering from orsuspected of having a neuropsychiatric condition. Defects in LTD includefor example a decrease in LTD or an increase in LTD in any region of thebrain (e.g., the temporal lobe, parietal lobe, the frontal cortex, thecingulate gyrus, the prefrontal cortex, the cortex, or the hippocampusor any other region in the brain or a combination thereof) in anindividual suffering from or suspected of having a neuropsychiatriccondition.

In some embodiments of the methods, administration of a PAK inhibitor(e.g., a compound of Formula I-X) modulates synaptic function (e.g.,synaptic transmission and/or plasticity) by increasing long termpotentiation (LTP) in an individual suffering from or suspected ofhaving a neuropsychiatric condition. In some embodiments of the methodsdescribed herein, administration of a PAK inhibitor (e.g., a compound ofFormula I-X) to an individual in need thereof modulates synapticfunction (e.g., synaptic transmission and/or plasticity) by increasinglong term potentiation (LTP) in the prefrontal cortex, or the cortex, orthe hippocampus or any other region in the brain or a combinationthereof. In some embodiments of the methods described herein,administration of a PAK inhibitor modulates synaptic function (e.g.,synaptic transmission and/or plasticity) by decreasing long termdepression (LTD) in an individual suffering from or suspected of havinga neuropsychiatric condition. In some embodiments of the methodsdescribed herein, administration of a PAK inhibitor to an individual inneed thereof modulates synaptic function (e.g., synaptic transmissionand/or plasticity) by decreasing long term depression (LTD) in thetemporal lobe, parietal lobe, the frontal cortex, the cingulate gyrus,the prefrontal cortex, the cortex, or the hippocampus or any otherregion in the brain or a combination thereof.

In some embodiments of the methods described herein, administration of aPAK inhibitor reverses defects in synaptic function (i.e. synaptictransmission and/or synaptic plasticity, induced by soluble Abeta dimersor oligomers. In some embodiments of the methods described herein,administration of a PAK inhibitors reverses defects in synaptic function(i.e. synaptic transmission and/or synaptic plasticity, induced byinsoluble Abeta oligomers and/or Abeta-containing plaques.

Provided herein are methods for stabilization of synaptic plasticitycomprising administering to an individual in need thereof (e.g., anindividual suffering from or suspected of having a neuropsychiatriccondition) a therapeutically effective amount of a PAK inhibitor (e.g.,a compound of Formula I-X). In some embodiments of the methods describedherein, administration of a PAK inhibitor stabilizes LTP or LTDfollowing induction (e.g., by theta-burst stimulation, high-frequencystimulation for LTP, low-frequency (e.g., 1 Hz) stimulation for LTD).

Provided herein are methods for stabilization of synaptic transmissioncomprising administering to an individual in need thereof (e.g., anindividual suffering from or suspected of having a neuropsychiatriccondition) a therapeutically effective amount of a PAK inhibitor (e.g.,a compound of Formula I-X). In some embodiments of the methods describedherein, administration of a PAK inhibitor stabilizes LTP or LTDfollowing induction (e.g., by theta-burst stimulation, high-frequencystimulation for LTP, low-frequency (e.g., 1 Hz) stimulation for LTD).

Also provided herein are methods for alleviation or reversal of corticalhypofrontality during performance of a cognitive task comprisingadministering to an individual in need thereof (e.g., an individualsuffering from or suspected of having a neuropsychiatric condition) atherapeutically effective amount of a PAK inhibitor (e.g., a compound ofFormula I-X). In some embodiments of the methods described herein,administration of a PAK inhibitor to an individual suffering from orsuspected of having a neuropsychiatric condition alleviates deficits inthe frontal cortex, for example deficits in frontal cortical activation,during the performance of a cognitive task (e.g., a Wisconsin Card Sorttest, Mini-Mental State Examination (MMSE), MATRICS cognitive battery,BACS score, Alzheimer's disease Assessment Scale—Cognitive Subscale(ADAS-Cog), Alzheimer's disease Assessment Scale—Behavioral Subscale(ADAS-Behav), Hopkins Verbal Learning Test-Revised or the like) andimproves cognition scores of the individual.

Provided herein are methods for reversing abnormalities in dendriticspine morphology or synaptic function that are caused by mutations inhigh-risk genes (e.g. mutations in Amyloid Precursor Protein (APP),mutations in presenilin 1 and 2, the epsilon4 allele, the 91 by allelein the telomeric region of 12q, Apolipoprotein E-4 (APOE4) gene, SORL1gene, reelin gene, DISC1 gene, or any other high-risk allele) comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a PAK inhibitor (e.g., a compound of Formula I-X).In some embodiments of the methods described herein, prophylacticadministration of a PAK inhibitor to an individual at a high risk fordeveloping a neuropsychiatric condition (e.g., a mutation in a DISC1gene pre-disposes the individual to schizophenia, a mutation in an APOE4gene pre-disposes the individual to Alzheimer's disease) reversesabnormalities in dendritic spine morphology and/or synaptic function andprevents development of the neuropsychiatric condition.

Provided herein are methods for stabilizing, reducing or reversingabnormalities in dendritic spine morphology or synaptic function thatare caused by increased activation of PAK at the synapse, comprisingadministration of a therapeutically effective amount of a PAK inhibitor(e.g., a compound of Formula I-X) to an individual in need thereof(e.g., an individual suffering from or suspected of having aneuropsychiatric condition). In some embodiments of the methodsdescribed herein, increased activation of PAK at the synapse is causedby Abeta. In some instances, increased activation of PAK at the synapseis caused by redistribution of PAK from the cytosol to the synapse. Insome embodiments of the methods described herein, administration of atherapeutically effective amount of a PAK inhibitor (e.g., a compound ofFormula I-X) to an individual in need thereof (e.g., an individualsuffering from or suspected of having a neuropsychiatric condition)reduces or prevents redistribution of PAK from the cytosol to thesynapse in neurons, thereby stabilizing, reducing or reversingabnormalities in dendritic spine morphology or synaptic function thatare caused by increased activation of PAK at the synapse.

Provided herein are methods for delaying the onset of a neuropsychiatriccondition comprising administering to an individual in need thereof(e.g., an individual with a high-risk allele for a NC) a therapeuticallyeffective amount of a PAK inhibitor (e.g., a compound of Formula I-X).Provided herein are methods for delaying the loss of dendritic spinedensity comprising administering to an individual in need thereof (e.g.,an individual with a high-risk allele for a NC) a therapeuticallyeffective amount of a PAK inhibitor. Provided herein are methods formodulation of spine density, shape, spine length, spine head volume, orspine neck diameter or the like comprising administering to anindividual in need thereof (e.g., an individual suffering from orsuspected of having a neuropsychiatric condition) a therapeuticallyeffective amount of a PAK inhibitor (e.g., a compound of Formula I-X).Provided herein are methods of modulating the ratio of mature dendriticspines to immature dendritic spines comprising administering to anindividual in need thereof (e.g., an individual suffering from orsuspected of having a neuropsychiatric condition) a therapeuticallyeffective amount of a PAK inhibitor. Provided herein are methods ofmodulating the ratio of dendritic spines head volume to dendritic spineslength comprising administering to an individual in need thereof (e.g.,an individual suffering from or suspected of having a neuropsychiatriccondition) a therapeutically effective amount of a PAK inhibitor (e.g.,a compound of Formula I-X).

In some embodiments of the methods described herein, administration of aPAK inhibitor (e.g., a maintenance dose of a PAK inhibitor) reduces theincidence of recurrence of one or more symptoms or pathologies in anindividual (e.g., recurrence of psychotic episodes, epileptic seizuresor the like). In some embodiments of the methods described herein,administration of a PAK inhibitor causes substantially completeinhibition of PAK and restores dendritic spine morphology and/orsynaptic function to normal levels. In some embodiments of the methodsdescribed herein, administration of a PAK inhibitor causes partialinhibition of PAK and restores dendritic spine morphology and/orsynaptic function to normal levels.

Provided herein are methods for stabilizing, reducing or reversingneuronal withering and/or atrophy or nervous tissue and/or degenerationof nervous tissue that is associated with a neuropsychiatric condition.In some embodiments of the methods described herein, administration of aPAK inhibitor to an individual suffering from or suspected of having aneuropsychiatric condition (e.g., Alzheimer's disease, Parkinson'sdisease or the like) stabilizes, alleviates or reverses neuronalwithering and/or atrophy and/or degeneration in the temporal lobe,parietal lobe, the frontal cortex, the cingulate gyrus or the like. Insome embodiments of the methods described herein, administration of aPAK inhibitor to an individual suffering from or suspected of having aneuropsychiatric condition stabilizes, reduces or reverses deficits inmemory and/or cognition and/or control of bodily functions.

In some instances, an NC is associated with a decrease in dendriticspine density. In some embodiments of the methods described herein,administration of a PAK inhibitor increases dendritic spine density. Insome instances, an NC is associated with an increase in dendritic spinelength. In some embodiments of the methods described herein,administration of a PAK inhibitor decreases dendritic spine length. Insome instances, an NC is associated with a decrease in dendritic spineneck diameter. In some embodiments of the methods described herein,administration of a PAK inhibitor increases dendritic spine neckdiameter. In some instances, an NC is associated with a decrease indendritic spine head diameter and/or dendritic spine head surface areaand/or dendritic spine head volume. In some embodiments of the methodsdescribed herein, administration of a PAK inhibitor increases dendriticspine head diameter and/or dendritic spine head volume and/or dendriticspine head surface area.

In some instances, an NC is associated with an increase in immaturespines and a decrease in mature spines. In some embodiments of themethods described herein, administration of a PAK inhibitor modulatesthe ratio of immature spines to mature spines. In some instances, an NCis associated with an increase in stubby spines and a decrease inmushroom-shaped spines. In some embodiments of the methods describedherein, administration of a PAK inhibitor modulates the ratio of stubbyspines to mushroom-shaped spines.

In some embodiments of the methods described herein, administration of aPAK inhibitor modulates a spine:head ratio, e.g., ratio of the volume ofthe spine to the volume of the head, ratio of the length of a spine tothe head diameter of the spine, ratio of the surface area of a spine tothe surface area of the head of a spine, or the like, compared to aspine:head ratio in the absence of a PAK inhibitor. In certainembodiments, a PAK inhibitor suitable for the methods described hereinmodulates the volume of the spine head, the width of the spine head, thesurface area of the spine head, the length of the spine shaft, thediameter of the spine shaft, or a combination thereof. In someembodiments, provided herein is a method of modulating the volume of aspine head, the width of a spine head, the surface area of a spine head,the length of a spine shaft, the diameter of a spine shaft, or acombination thereof, by contacting a neuron comprising the dendriticspine with an effective amount of a PAK inhibitor described herein. Inspecific embodiments, the neuron is contacted with the PAK inhibitor invivo.

In certain embodiments, a compound or a composition comprising acompound described herein is administered for prophylactic and/ortherapeutic treatments. In therapeutic applications, the compositionsare administered to an individual already suffering from a disease orcondition, in an amount sufficient to cure or at least partially arrestthe symptoms of the disease or condition. In various instances, amountseffective for this use depend on the severity and course of the diseaseor condition, previous therapy, an individual's health status, weight,and response to the drugs, and the judgment of the treating physician.

In some embodiments, a composition containing a therapeuticallyeffective amount of a PAK inhibitor is administered prophylactically toan individual that while not overtly manifesting symptoms of aneuropsychiatric condition has been identified as having a high risk ofdeveloping a neuropsychiatric condition, e.g., an individual isidentified as being a carrier of a mutation or polymorphism associatedwith a higher risk to develop a neuropsychiatric condition (see, e.g.,Hall et al (2006), Nat. Neurosci., 9(12):1477-8), or an individual thatis from a family that has a high incidence of neuropsychiatricconditions. In some embodiments, MRI is used to detect brainmorphological changes in individuals prior to the onset of disease (see,e.g., Toga et al (2006), TINS, 29(3):148-159). For example, in someinstances, the typical age of onset for schizophrenia is post-puberty.In some instances, the typical age of onset for schizophrenia is between20-28 for males and 26-32 for females. For example, in some instances, atypical age of onset for Alzheimer's disease is about 55-80 years.Accordingly, in some embodiments, a PAK inhibitor is administeredprophylactically to an individual at risk between about 1 to about 10years, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years prior to anestablished and/or typical age range of onset for a neuropsychiatriccondition.

In prophylactic applications, compounds or compositions containingcompounds described herein are administered to an individual susceptibleto or otherwise at risk of a particular disease, disorder or condition.In certain embodiments of this use, the precise amounts of compoundadministered depend on an individual's state of health, weight, and thelike. Furthermore, in some instances, when a compound or compositiondescribed herein is administered to an individual, effective amounts forthis use depend on the severity and course of the disease, disorder orcondition, previous therapy, an individual's health status and responseto the drugs, and the judgment of the treating physician.

In certain instances, wherein following administration of a selecteddose of a compound or composition described herein, an individual'scondition does not improve, upon the doctor's discretion theadministration of a compound or composition described herein isoptionally administered chronically, that is, for an extended period oftime, including throughout the duration of an individual's life in orderto ameliorate or otherwise control or limit the symptoms of anindividual's disorder, disease or condition.

In certain embodiments, an effective amount of a given agent variesdepending upon one or more of a number of factors such as the particularcompound, disease or condition and its severity, the identity (e.g.,weight) of an individual or host in need of treatment, and is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and an individual or hostbeing treated. In some embodiments, doses administered include those upto the maximum tolerable dose. In certain embodiments, about 0.02-5000mg per day, from about 1-1500 mg per day, about 1 to about 100 mg/day,about 1 to about 50 mg/day, or about 1 to about 30 mg/day, or about 5 toabout 25 mg/day of a compound described herein is administered. Invarious embodiments, the desired dose is conveniently be presented in asingle dose or in divided doses administered simultaneously (or over ashort period of time) or at appropriate intervals, for example as two,three, four or more sub-doses per day.

In certain instances, there are a large number of variables in regard toan individual treatment regime, and considerable excursions from theserecommended values are considered within the scope described herein.Dosages described herein are optionally altered depending on a number ofvariables such as, by way of non-limiting example, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of an individual individual, theseverity of the disease or condition being treated, and the judgment ofthe practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens areoptionally determined by pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. In certainembodiments, data obtained from cell culture assays and animal studiesare used in formulating a range of dosage for use in human. In specificembodiments, the dosage of compounds described herein lies within arange of circulating concentrations that include the ED₅₀ with minimaltoxicity. The dosage optionally varies within this range depending uponthe dosage form employed and the route of administration utilized.

Combination Therapy

In some embodiments, one or more PAK inhibitors are used in combinationwith one or more other therapeutic agents to treat an individualsuffering from a neuropsychiatric condition. The combination of PAKinhibitors with a second therapeutic agent (e.g., a typical or atypicalantipsychotic agent, an mGluR1 antagonist, an mGluR5 antagonist, anmGluR5 potentiator, a mGluR2 agonist, an alpha7 nicotinic receptoragonist or potentiator, an antioxidant, a neuroprotectant, a trophicfactor, an anticholinergic, a beta-secretase inhibitor or the like)allows a reduced dose of both agents to be used thereby reducing thelikelihood of side effects associated with higher dose monotherapies. Inone embodiment, the dose of a second active agent is reduced in thecombination therapy by at least 50% relative to the correspondingmonotherapy dose, whereas the PAK inhibitor dose is not reduced relativeto the monotherapy dose; in further embodiments, the reduction in doseof a second active agent is at least 75%; in yet a further embodiment,the reduction in dose of a second active agent is at least 90%. In someembodiments, the second therapeutic agent is administered at the samedose as a monotherapy dose, and the addition of a PAK inhibitor to thetreatment regimen alleviates symptoms of an NC that are not treated bymonotherapy with the second therapeutic agent. Symptoms and diagnosticcriteria for all of the conditions mentioned above are described indetail in the Diagnostic and Statistical Manual of Mental Disorders,fourth edition, American Psychiatric Association (2005) (DSM-IV).

In some embodiments, the combination of a PAK inhibitor and a secondtherapeutic agent is synergistic (e.g., the effect of the combination isbetter than the effect of each agent alone). In some embodiments, thecombination of a PAK inhibitor and a second therapeutic agent isadditive (e.g., the effect of the combination of active agents is aboutthe same as the effect of each agent alone). In some embodiments, anadditive effect is due to the PAK inhibitor and the second therapeuticagent modulating the same regulatory pathway. In some embodiments, anadditive effect is due to the PAK inhibitor and the second therapeuticagent modulating different regulatory pathways. In some embodiments, anadditive effect is due to the PAK inhibitor and the second therapeuticagent treating different symptom groups of the NC (e.g., a PAK inhibitortreats negative symptoms and the second therapeutic agent treatspositive symptoms of schizophrenia). In some embodiments, administrationof a second therapeutic agent treats the remainder of the same ordifferent symptoms or groups of symptoms that are not treated byadministration of a PAK inhibitor alone.

In some embodiments, administration of a combination of a PAK inhibitorand a second therapeutic agent alleviates side effects that are causedby the second therapeutic agent (e.g., side effects caused by anantipsychotic agent or a nootropic agent). In some embodiments,administration of the second therapeutic agent inhibits metabolism of anadministered PAK inhibitor (e.g., the second therapeutic agent blocks aliver enzyme that degrades the PAK inhibitor) thereby increasingefficacy of a PAK inhibitor. In some embodiments, administration of acombination of a PAK inhibitor and a second therapeutic agent (e.g. asecond agent that modulates dendritic spine morphology (e.g.,minocyline)) improves the therapeutic index of a PAK inhibitor.

Agents for Treating Psychotic Disorders

Where a subject is suffering from or at risk of suffering from apsychotic disorder (e.g., schizophrenia), a PAK inhibitor compositiondescribed herein is optionally used together with one or more agents ormethods for treating a psychotic disorder in any combination.Alternatively, a PAK inhibitor composition described herein isadministered to a patient who has been prescribed an agent for treatinga psychotic disorder. In some embodiments, administration of a PAKinhibitor in combination with an antipsychotic agent has a synergisticeffect and provides an improved therapeutic outcome compared tomonotherapy with antipsychotic agent or monotherapy with PAK inhibitor.Alternatively, a PAK inhibitor composition described herein isadministered to a patient who is non-responsive to, or beingunsatisfactorily treated with an antipsychotic agent.

Examples of therapeutic agents/treatments for treating a psychoticdisorder include, but are not limited to, any of the following: typicalantipsychotics, e.g., Chlorpromazine (Largactil, Thorazine),Fluphenazine (Prolixin), Haloperidol (Haldol, Serenace), Molindone,Thiothixene (Navane), Thioridazine (Mellaril), Trifluoperazine(Stelazine), Loxapine, Perphenazine, Prochlorperazine (Compazine,Buccastem, Stemetil), Pimozide (Orap), Zuclopenthixol; and atypicalantipsychotics, e.g., LY2140023, Clozapine, Risperidone, Olanzapine,Quetiapine, Ziprasidone, Aripiprazole, Paliperidone, Asenapine,Iloperidone, Sertindole, Zotepine, Amisulpride, Bifeprunox, andMelperone.

Agents for Treating Mood Disorders

Where a subject is suffering from or at risk of suffering from a mooddisorder (e.g., clinical depression), a PAK inhibitor compositiondescribed herein is optionally used together with one or more agents ormethods for treating a mood disorder in any combination. Alternatively,a PAK inhibitor composition described herein is administered to apatient who has been prescribed an agent for treating a mood disorder.Alternatively, a PAK inhibitor composition described herein isadministered to a patient who is non-responsive to or beingunsatisfactorily treated with an agent for treating a mood disorder.

Examples of therapeutic agents/treatments for treating a mood disorderinclude, but are not limited to, any of the following: selectiveserotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa),escitalopram (Lexapro, Esipram), fluoxetine (Prozac), paroxetine (Paxil,Seroxat), sertraline (Zoloft), fluvoxamine (Luvox);serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine(Effexor), desvenlafaxine, nefazodone, milnacipran, duloxetine(Cymbalta), bicifadine; tricyclic antidepressants such as amitriptyline,amoxapine, butriptyline, clomipramine, desipramine, dosulepin, doxepin,impramine, lofepramine, nortriptyline; monoamine oxidase inhibitors(MAOIs) such as isocarboxazid, linezolid, moclobemide, nialamide,phenelzine, selegiline, tranylcypromine, trimipramine; and other agentssuch as mirtazapine, reboxetine, viloxazine, malprotiline, andbupropion.

Agents for Treating Epilepsy

Where a subject is suffering from or at risk of suffering from epilepsy,a PAK inhibitor composition described herein is optionally used togetherwith one or more agents or methods for treating epilepsy in anycombination. Alternatively, a PAK inhibitor composition described hereinis administered to a patient who has been prescribed an agent fortreating epilepsy. Alternatively, a PAK inhibitor composition describedherein is administered to a patient who is refractory to or beingunsatisfactorily treated with an agent for treating epilepsy.

Examples of therapeutic agents/treatments for treating epilepsy include,but are not limited to, any of the following: carbamazepine, clobazam,clonazepam, ethosuximide, felbamate, fosphenyloin, gabapentin,lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenyloin,pregabalin, primidone, sodium valproate, tiagabine, topiramate,valproate semisodium, valproic acid, vigabatrin, and zonisamide.

Agents for Treating Huntington's Disease

Where a subject is suffering from or at risk of suffering fromHuntingtin's disease, a PAK inhibitor composition described herein isoptionally used together with one or more agents or methods for treatingHuntingtin's disease in any combination. Alternatively, a PAK inhibitorcomposition described herein is administered to a patient who has beenprescribed an agent for treating Huntington's disease. Alternatively, aPAK inhibitor composition described herein is administered to a patientwho is refractory to or being unsatisfactorily treated with an agent fortreating Huntington's disease.

Examples of therapeutic agents/treatments for treating Huntingtin'sdisease include, but are not limited to, any of the following: omega-3fatty acids, miraxion, Haloperidol, dopamine receptor blockers,creatine, cystamine, cysteamine, clonazepam, clozapine, Coenzyme Q10,minocycline, antioxidants, antidepressants (notably, but notexclusively, selective serotonin reuptake inhibitors SSRIs, such assertraline, fluoxetine, and paroxetine), select dopamine antagonists,such as tetrabenazine; and RNAi knockdown of mutant huntingtin (mHtt).

Agents for Treating Parkinson's Disease

Where a subject is suffering from or at risk of suffering fromParkinson's Disease, a PAK inhibitor composition described herein isoptionally used together with one or more agents or methods for treatingParkinson's disease in any combination. Alternatively, a PAK inhibitorcomposition described herein is administered to a patient who has beenprescribed an agent for treating Parkinson's disease. Alternatively, aPAK inhibitor composition described herein is administered to a patientwho is refractory to or being unsatisfactorily treated with an agent fortreating Parkinson's disease.

Examples of therapeutic agents/treatments for treating Parkinson'sDisease include, but are not limited to any of the following: L-dopa,carbidopa, benserazide, tolcapone, entacapone, bromocriptine, pergolide,pramipexole, ropinirole, cabergoline, apomorphine, lisuride, selegiline,or rasagiline

Group I mGluR Antagonists

In some embodiments, one or more PAK inhibitors are used in combinationwith one or more Group I metabotropic glutamate receptor (mGluR)antagonists (e.g., mGluR5 antagonists) to treat an individual sufferingfrom a neuropsychiatric condition. The combination of PAK inhibitorswith Group I mGluR antagonists allows a reduced dose of both agents tobe used thereby reducing the likelihood of side effects associated withhigher dose monotherapies.

In some embodiments, reduction of signaling from a Group I mGluR(mGluR5) in vivo by genetic engineering (using mGluR5 knock-outheterozygote animals) leads to a reversal of the dendritic spine andbehavioral defects. In some instances, where an individual is sufferingfrom or at risk of suffering from a neuropsychiatric condition, a PAKinhibitor composition described herein is optionally used together withone or Group I mGluR antagonists. Group I mGluR antagonists includeantagonists that are mGluR1-selective antagonists, mGluR5-selectiveantagonists, or antagonists that antagonize both mGluR1 and mGluR5. Insome embodiments, a PAK inhibitor composition is used in combinationwith an mGluR5-selective antagonist. In some embodiments, a PAKinhibitor composition is used in combination with an mGluRlselectiveantagonist. In some embodiments, a PAK inhibitor composition is used incombination with a Group I mGluR antagonist that antagonizes both mGluR1and mGluR5 (i.e., an antagonist that is not selective for mGluR1 ormGluR5). As used herein, the term “selective antagonist” indicates thatthe antagonist has an ED₅₀ for antagonizing a first receptor (e.g.,mGluR5) that is at least about 10 fold to about 1000 fold lower, e.g.,11, 20, 30, 40, 50, 100, 105, 125, 135, 150, 200, 300, 400, 500, 600,700, 800, 900, or any other fold lower from about 10 fold to about 1000fold lower than the ED₅₀ for antagonism of a second receptor (e.g.,mGluR1).

Examples of Group I mGluR antagonists include, but are not limited to,any of the following (E)-6-methyl-2-styryl-pyridine (SIB 1893),6-methyl-2-(phenylazo)-3-pyridinol,.alpha.-methyl-4-carboxyphenylglycine (MCPG), or2-methyl-6-(phenylethynyl)-pyridine (MPEP). Examples of Group I mGluRantagonists also include those described in, e.g., U.S. patentapplication Ser. Nos. 10/076,618; 10/211,523; and 10/766,948. Examplesof mGluR5-selective antagonists include, but are not limited to thosedescribed in, e.g., U.S. Pat. No. 7,205,411 and U.S. patent applicationSer. No. 11/523,873. Examples of mGluR1-selective antagonists include,but are not limited to, those described in, e.g., U.S. Pat. No.6,482,824.

In some embodiments, the mGluR Group I antagonist is AIDA(1-aminoindan-1,5-dicarboxylic acid); ACDPP(3-Amino-6-chloro-5-dimethylamino-N-2-pyridinylpyrazine carboxamidehydrochloride; DL-AP3 (DL-2-Amino-3-phosphonopropionic acid);BAY-36-7620((3aS,6aS)-Hexahydro-5-methylene-6a-(2-naphthalenylmethyl)-1H-cyclopenta[c]furan-1-one);Fenobam; 4 CPG ((S)-4-carboxyphenylglycine); (S)-4C3HPG((S)-4-carboxy-3-hydroxyphenylglycine); CPCCOEt(7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester); LY367385 ((S)-(+)-a-Amino-4-carboxy-2-methylbenzeneacetic acid); LY 456236hydrochloride (6-methoxy-N-(4-methoxyphenyl) quinazolin-4-amine, MPMQhydrochloride); 3-MATIDA (a-Amino-5-carboxy-3-methyl-2-thiopheneaceticacid); MCPG (α-methyl-4-carboxyphenylglycine); MPEP(2-methyl-6-(phenylethynyl)-pyridine); (MTEP)3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine;PHCCC(N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carbox amide; SIB1757 (6-Methyl-2-(phenylazo)-3-pyridinol; SIB 1893(2-Methyl-6-(2-phenylethenyl)pyridine; YM 298198 hydrochloride(6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamidehydrochloride);(YM-193167(6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide);(NPS 2390 (Quinoxaline-2-carboxylic acid adamantan-1-ylamide);3-(5-(pyridin-2-yl)-2H-tetrazol-2-yl)benzonitrile;3-[3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine;3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile;N-cyclohexyl-6-{[(2-methoxyethyl)(methyl)amino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide(YM-202074); Desmethyl-YM298198(6-Amino-N-cyclohexyl-3-methylthiazolo[3,2-a]benzimidazole-2-carboxamidehydrochloride); MPEP hydrochloride (2-Methyl-6-(phenylethynyl)pyridinehydrochloride); (S)-MCPG ((S)-a-Methyl-4-carboxyphenylglycine);(RS)-MCPG ((RS)-a-Methyl-4-carboxyphenylglycine); E4CPG((RS)-a-Ethyl-4-carboxyphenylglycine); Hexylhomoibotenic acid(a-Amino-4-hexyl-2,3-dihydro-3-oxo-5-isoxazolepropanoic acid;HexylHIBO); (S)-Hexylhomoibotenic acid((S)-a-Amino-4-hexyl-2,3-dihydro-3-oxo-5-isoxazolepropanoic acid;(S)-HexylHIBO); EMQMCM(3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanonemethanesulfonate); JNJ 16259685; R214127(1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone);(S)-3-Carboxy-4-hydroxyphenylglycine ((S)-3C4HPG); Anti-mGlu5 blockingpeptide ([K]-SSPKYDTLIIRDYTQSSSSL); DFB (3,3′-Difluorobenzaldazine);DMeOB ([(3-Methoxyphenyl)methylene]hydrazone-3-methoxybenzalde hyde);Anti-mGIu₅ (([K]-SSPKYDTLIIRDYTQSSSSL); reluzole; or combinationsthereof.

In some embodiments, the modulator of a Group I mGluR isS-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone(ADX47273) (Positive allosteric modulator);4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide(FTIDC); 6-(3-methoxy-4-(pyridin-2-yl)phenyl)imidazole[2,1-b]thiazole;2-(2-methoxy-4-(4-(pyridin-2-yl)oxazol-2-yl)phenyl)acetonitrile;2-(4-(benzo[d]oxazol-2-yl)-2-methoxyphenyl)acetonitrile;2-(4-(2,3-dihydro-1H-inden-2-ylamino)4a,5,6,7,8,8a-hexahydroquinazolin-2ylthio)ethanol;or combinations thereof.

In some embodiments, where a Group I mGluR antagonist (e.g., an mGluR5antagonist) is administered in combination with a PAK inhibitor, thedose of the Group I mGluR antagonist ranges from about 0.001 mg/kg/dayto about 30.0 mg/kg/day, e.g., about 0.005 mg/kg/day, 0.009 mg/kg/day,0.010 mg/kg/day, 0.050 mg/kg/day, 0.20 mg/kg/day, 0.50 mg/kg/day, 0.75mg/kg/day, 1.0 mg/kg/day, 2.0 mg/kg/day, 3.5 mg/kg/day, 4.5 mg/kg/day,5.0 mg/kg/day, 6.2 mg/kg/day, 6.8 mg/kg/day, 7.0 mg/kg/day, 10.0mg/kg/day, 15 mg/kg/day, 20 mg/kg/day, 25 mg/kg/day, or any other dosefrom about 0.001 mg/kg/day to about 10.0 mg/kg/day, from about 0.001mg/kg/day to about 20.0 mg/kg/day, or from about 0.01 mg/kg/day to about20.0 mg/kg/day.

In some embodiments, the combination treatment comprises administering acombined dosage form that is a pharmacological composition comprising atherapeutically effective amount of a PAK inhibitor and a Group I mGluRantagonist (e.g., an mGluR5-selective antagonist) as described herein.In some embodiments, the pharmacological composition comprises a PAKinhibitor compound and an mGluR5-selective antagonist selected from U.S.Pat. No. 7,205,411.

mGluR Agonists

In some embodiments, a second therapeutic agent used in combination witha PAK inhibitor is a Group I mGluR1 agonist. Examples of mGluR1 agonistsand/or mGluR1 potentiators include and are not limited to ACPT-I((1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid); L-AP4(L-(+)-2-Amino-4-phosphonobutyric acid); (S)-3,4-DCPG((S)-3,4-dicarboxyphenylglycine); (RS)-3,4-DCPG((RS)-3,4-dicarboxyphenylglycine); (RS)-4-phosphonophenylglycine((RS)PPG); AMN082 (N′-bis(diphenylmethyl)-1,2-ethanediaminedihydrochloride); DCG-IV((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine) or the like. Insome embodiments, an mGluR1 agonist is AMN082. In some embodiments, asecond therapeutic agent is a mGluR2/3 agonist or mGluR2/3 potentiator.Examples of mGluR2/3 agonists include and are not limited to LY389795((−)-2-thia-4-aminobicyclo-hexane-4,6-dicarboxylate); LY379268((−)-2-oxa-4-aminobicyclo-hexane-4,6-dicarboxylate); LY354740((+)-2-aminobicyclo-hexane-2,6dicarboxylate); DCG-IV((2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine); 2R,4R-APDC(2R,4R-4-aminopyrrolidine-2,4-dicarboxylate), (S)-3C4HPG((S)-3-carboxy-4-hydroxyphenylglycine); (S)-4C3HPG((S)-4-carboxy-3-hydroxyphenylglycine); L-CCG-I((2S,1′S,2′S)-2-(carboxycyclopropyl)glycine); and/or combinationsthereof. Examples of mGluR2 agonists or mGluR2 potentiators include andare not limited to positive allosteric modulators of mGluR2, includingADX71149 (Addex Partner). Examples of mGluR5 agonists or mGluR5potentiators include and are not limited to MPEP,(RS)-2-chloro-5-hydroxyphenylglycine (CHPG),1S,3R-1-amino-1,3-cyclopentanedicarboxylate (ACPD) or the like.

Apha7 Nicotinic Receptor Modulators

In some embodiments, one or more PAK inhibitors are used in combinationwith one or more alpha7 nicotinic receptor modulators to treat anindividual suffering from a neuropsychiatric condition. Alpha7 nicotinicreceptor modulators include alpha7 nicotinic receptor agonists, alpha7nicotinic receptor antagonists, and/or alpha7 nicotinic receptormodulators positive allosteric potentiators. The combination of PAKinhibitors with alpha7 nicotinic receptor modulators allows a reduceddose of both agents to be used thereby reducing the likelihood of sideeffects associated with higher dose monotherapies.

Examples of alpha7 nicotinic receptor agonists include and are notlimited to(+)—N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide,PHA-709829, PNU-282,987, A-582941, TC-1698, TC-5619, GTS-21, SSR180711,tropisetron or the like. Examples of alpha7 nicotinic receptorantagonists include α-conotoxin, quinolizidine or the like. Alpha7nicotinic receptor allosteric potentiators include PNU-120596, NS-1738,XY4083, A-867744, EVP-6124 (Envivo), or the like.

Anticholinergic Agents

Where a subject is suffering from or at risk of suffering fromAlzheimer's disease, a PAK inhibitor composition described herein isoptionally used together with one or more agents or methods for treatingAlzheimer's disease in any combination. In some embodiments, a PAKinhibitor composition described herein is administered to a patient whohas been prescribed an anticholinergic agent. In some embodiments,administration of a PAK inhibitor in combination with an anticholinergicagent has a synergistic effect and provides an improved therapeuticoutcome compared to monotherapy with anticholinergic agent ormonotherapy with PAK inhibitor. Alternatively, a PAK inhibitorcomposition described herein is administered to an individual who isnon-responsive to, or being unsatisfactorily treated with ananticholinergic agent. Example of anticholinergic drugs includeipratropium bromide (Atrovent), oxitropium bromide (Oxivent), tiotropium(Spiriva), are donepezil (Aricept), galantamine (Razadyne), rivastigmine(Exelon and Exelon Patch), physostigimine, scopolamine, orphenadrine,dicycloverine/dicyclomine or the like.

NMDA Receptor Antagonists

Where a subject is suffering from or at risk of suffering fromAlzheimer's disease, a PAK inhibitor composition described herein isoptionally used together with one or more agents or methods for treatingAlzheimer's disease in any combination. In some embodiments, a PAKinhibitor composition described herein is administered to a patient whohas been prescribed an NMDA receptor antagonist. Examples of NMDAreceptor antagonists useful in the methods and compositions describedherein include and are not limited to memantine.

Neuroprotectants

In some embodiments, a PAK inhibitor or a composition thereof describedherein is administered in combination with a neuroprotectant such as,for example, minocycline, resveratrol or the like.

Trophic Factors

In some embodiments, a PAK inhibitor or a composition thereof describedherein is administered in combination with a trophic agent including, byway of example, glial derived nerve factor (GDNF), brain derived nervefactor (BDNF) or the like.

Antioxidants

Where a subject is suffering from or at risk of suffering from aneuropsychiatric condition (e.g., Alzheimer's disease, Mild CognitiveImpairment), a PAK inhibitor composition described herein is optionallyused together with one or more agents or methods for treating theneuropsychiatric condition in any combination. In some embodiments, aPAK inhibitor composition described herein is administered to a patientwho is taking or has been prescribed an antioxidant. Examples ofantioxidants useful in the methods and compositions described hereininclude and are not limited to ubiquinone, aged garlic extract,curcumin, lipoic acid, beta-carotene, melatonin, resveratrol, Ginkgobiloba extract, vitamin C, viatmin E or the like.

Metal Protein Attenuating Compounds

Where a subject is suffering from or at risk of suffering from aneuropsychiatric condition (e.g., Alzheimer's disease, Parkinson'sdisease), a PAK inhibitor composition described herein is optionallyused together with one or more agents or methods for treating theneuropsychiatric condition in any combination. In some embodiments, aPAK inhibitor composition described herein is administered to a patientwho has been prescribed a Metal Protein Attenuating agent. Examples ofMetal Protein Attenuating agents useful in the methods and compositionsdescribed herein include and are not limited to 8-Hydroxyquinoline,iodochlorhydroxyquin or the like and derivatives thereof.

Beta-Secretase Inhibitors

Where a subject is suffering from or at risk of suffering from aneuropsychiatric condition (e.g., Alzheimer's disease), a PAK inhibitorcomposition described herein is optionally used together with one ormore agents or methods for treating the neuropsychiatric condition inany combination. In some embodiments, a PAK inhibitor compositiondescribed herein is administered to a patient who has been prescribed abeta secretase inhibitor. Examples of beta secretase inhibitors usefulin the methods and compositions described herein include and are notlimited to LY450139, 2-Aminoquinazolines compounds described in J. Med.Chem. 50 (18): 4261-4264, beta secretase inhibitors described thereinare incorporated herein by reference, or the like.

Gamma Secretase Inhibitors

Where a subject is suffering from or at risk of suffering from aneuropsychiatric condition (e.g., Alzheimer's disease), a PAK inhibitorcomposition described herein is optionally used together with one ormore agents or methods for treating the neuropsychiatric condition inany combination. In some embodiments, a PAK inhibitor compositiondescribed herein is administered to a patient who has been prescribed abeta secretase inhibitor. Examples of beta secretase inhibitors usefulin the methods and compositions described herein include and are notlimited to LY-411575,(2S)-2-hydroxy-3-methyl-N-((1S)-1-methyl-2-{[(1S)-3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1-yl]amino}-2-oxoethyl)butanamide(semagacestat), (R)-2-(3-Fluoro-4-phenylphenyl)propanoic acid(Tarenflurbil), or the like.

Antibodies

Where a subject is suffering from or at risk of suffering from aneuropsychiatric condition (e.g., Alzheimer's disease), a PAK inhibitorcomposition described herein is optionally used together with one ormore agents or methods for treating the neuropsychiatric condition inany combination. In some embodiments, a PAK inhibitor compositiondescribed herein is administered to a patient who has been prescribed anAbeta antibody. Examples of antibodies useful in the methods andcompositions described herein include and are not limited an Abetaantibody (e.g., bapineuzumab), PAK antibodies (e.g., ABIN237914) or thelike.

Other Agents

In some embodiments, one or more PAK inhibitors are used in combinationwith one or more agents that modulate dendritic spine morphology orsynaptic function. Examples of agents that modulate dendritic spinemorphology include minocycline, trophic factors (e.g., brain derivedneutrophic factor, glial cell-derived neurtrophic factor), oranesthetics that modulate spine motility, or the like. In someembodiments, one or more PAK inhibitors are used in combination with oneor more agents that modulate cognition. In some embodiments, a secondtherapeutic agent is a nootropic agent that enhances cognition. Examplesof nootropic agents include and are not limited to piracetam,pramiracetam, oxiracetam, and aniracetam.

Blood Brain Barrier Facilitators

In some instances, a PAK inhibitor is optionally administered incombination with a blood brain barrier facilitator. In certainembodiments, an agent that facilitates the transport of a PAK inhibitoris covalently attached to the PAK inhibitor. In some instances, PAKinhibitors described herein are modified by covalent attachment to alipophilic carrier or co-formulation with a lipophilic carrier. In someembodiments, a PAK inhibitor is covalently attached to a lipophiliccarrier, such as e.g., DHA, or a fatty acid. In some embodiments, a PAKinhibitor is covalently attached to artificial low density lipoproteinparticles. In some instances, carrier systems facilitate the passage ofPAK inhibitors described herein across the blood-brain barrier andinclude but are not limited to, the use of a dihydropyridine pyridiniumsalt carrier redox system for delivery of drug species across the bloodbrain barrier. In some instances a PAK inhibitor described herein iscoupled to a lipophilic phosphonate derivative. In certain instances,PAK inhibitors described herein are conjugated to PEG-oligomers/polymersor aprotinin derivatives and analogs. In some instances, an increase ininflux of a PAK inhibitor described herein across the blood brainbarrier is achieved by modifying A PAK inhibitor described herein (e.g.,by reducing or increasing the number of charged groups on the compound)and enhancing affinity for a blood brain barrier transporter. In certaininstances, a PAK inhibitor is co-administered with an an agent thatreduces or inhibits efflux across the blood brain barrier, e.g. aninhibitor of P-glycoprotein pump (PGP) mediated efflux (e.g.,cyclosporin, SCH66336 (lonafarnib, Schering)).

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with, e.g., compounds described in U.S. Pat.Nos. 5,863,532, 6,191,169, 6,248,549, and 6,498,163; U.S. PatentApplications 200200045564, 20020086390, 20020106690, 20020142325,20030124107, 20030166623, 20040091992, 20040102623, 20040208880,200500203114, 20050037965, 20050080002, and 20050233965, 200.60088897;EP Patent Publication 1492871; PCT patent publication WO 9902701; PCTpatent publication WO 2008/047307; Kumar et al., (2006), Nat. Rev.Cancer, 6:459; and Eswaran et al., (2007), Structure, 15:201-213, all ofwhich are incorporated herein by reference for disclosure of kinaseinhibitors and/or PAK inhibitors described therein.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with compounds including and not limited toBMS-387032; SNS-032; CHI4-258; TKI-258; EKB-569; JNJ-7706621; PKC-412;staurosporine; SU-14813; sunitinib;N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine(gefitinib), VX-680; MK-0457; combinations thereof; or salts, prodrugsthereof.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a polypeptide comprising an amino acidsequence about 80% to about 100% identical, e.g., 85%, 90%, 92%, 93%,95%, 96%, 97%, 98%, 99%, or any other percent from about 80% to about100% identical the following amino acid sequence:

HTIHVGFDAVTGEFTGMPEQWARLLQTSNITKSEQKKNPQAVLDVLE FYNSKKTSNSQ KYMSFTDKS

The above sequence corresponds to the PAK autoinhibitory domain (PAD)polypeptide amino acids 83-149 of PAK1 polypeptide as described in,e.g., Zhao et al (1998). In some embodiments, the PAK inhibitor is afusion protein comprising the above-described PAD amino acid sequence.In some embodiments, in order to facilitate cell penetration the fusionpolypeptide (e.g., N-terminal or C-terminal) further comprises apolybasic protein transduction domain (PTD) amino acid sequence, e.g.:RKKRRQRR; YARAAARQARA; THRLPRRRRRR; or GGRRARRRRRR.

In some embodiments, in order to enhance uptake into the brain, thefusion polypeptide further comprises a human insulin receptor antibodyas described in U.S. patent application Ser. No. 11/245,546.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a peptide inhibitor comprising asequence at least 60% to 100%, e.g., 65%, 70%, 75%, 80%, 85%, 90%, 92%,93%, 95%, 96%, 97%, 98%, 99%, or any other percent from about 60% toabout 100% identical the following amino acid sequence:PPVIAPREHTKSVYTRS as described in, e.g., Zhao et al (2006), NatNeurosci, 9(2):234-242. In some embodiments, the peptide sequencefurther comprises a PTD amino acid sequence as described above.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a polypeptide comprising an amino acidsequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%, 96%, 97%,98%, 99%, or any other percent from about 80% to about 100% identical tothe FMRP1 protein (GenBank Accession No. Q06787), where the polypeptideis able to bind with a PAK (for example, PAK1, PAK2, PAK3, PAK4, PAK5and/or PAK6). In some embodiments compounds of Formulae (I-X) areoptionally administered in combination with a polypeptide comprising anamino acid sequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%,96%, 97%, 98%, 99%, or any other percent from about 80% to about 100%identical to the FMRPI protein (GenBank Accession No. Q06787), where thepolypeptide is able to bind with a Group I PAK, such as, for example PAKI (see, e.g., Hayashi et al (2007), Proc Natl Acad Sci USA,104(27):11489-11494. In some embodiments, compounds of Formulae (I-X)are optionally administered in combination with a polypeptide comprisinga fragment of human FMRP1 protein with an amino acid sequence at least80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%, 96%, 97%, 98%, 99%, or anyother percent from about 80% to about 100% identical to the sequence ofamino acids 207-425 of the human FMRPI protein (i.e., comprising the KH1and KH2 domains), where the polypeptide is able to bind to PAK1.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a polypeptide comprising an amino acidsequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%, 96%, 97%,98%, 99%, or any other percent from about 80% to about 100% identical toat least five, at least ten at least twenty, at least thirty, at leastforty, at least fifty, at least sixty, at least seventy, at leasteighty, at least ninety contiguous amino acids of the huntingtin (htt)protein (GenBank Accession No. NP 002102, gi 90903231), where thepolypeptide is able to bind to a Group I PAK (for example, PAK1, PAK2,and/or PAK3). In some embodiments, compounds of Formulae (I-X) areoptionally administered in combination with a polypeptide comprising anamino acid sequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%,96%, 97%, 98%, 99%, or any other percent from about 80% to about 100%identical to at least a portion of the huntingtin (htt) protein (GenBankAccession No. NP 002102, gi 90903231), where the polypeptide is able tobind to PAK1. In some embodiments, compounds of Formulae (I-X) areoptionally administered in combination with a polypeptide comprising afragment of human huntingtin protein with an amino acid sequence atleast 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%, 96%, 97%, 98%, 99%, orany other percent from about 80% to about 100% identical to a sequenceof at least five, at least ten, at least twenty, at least thirty, atleast forty, at least fifty, at least sixty, at least seventy, at leasteighty, at least ninety, or at least 100 contiguous amino acids of thehuman huntingtin protein that is outside of the sequence encoded by exon1 of the htt gene (i.e., a fragment that does not contain poly glutamatedomains), where the polypeptide binds a PAK. In some embodiments,compounds of Formulae (I-X) are optionally administered in combinationwith a polypeptide comprising a fragment of human huntingtin proteinwith an amino acid sequence at least 80% identical to a sequence of thehuman huntingtin protein that is outside of the sequence encoded by exon1 of the htt gene (i.e., a fragment that does not contain poly glutamatedomains), where the polypeptide binds PAKI.

Upstream Regulators of p21 Activated Kinases

In certain embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with an indirect PAK modulator (e.g., anindirect PAK inhibitor) that affects the activity of a molecule thatacts in a signaling pathway upstream of PAK (upstream regulators ofPAK). Upstream effectors of PAK include, but are not limited to: TrkBreceptors; NMDA receptors; EphB receptors; adenosine receptors; estrogenreceptors; integrins; FMRP; Rho-family GTPases, including Cdc42, Rac(including but not limited to Rac1 and Rac2), CDK5, PI3 kinases, NCK,PDK1, EKT, GRB2, Chp, TC10, Tcl, and Wrch-1; guanine nucleotide exchangefactors (“GEFs”), such as but not limited to GEFT, members of the Dblfamily of GEFs, p21-activated kinase interacting exchange factor (PIX),DEF6, Zizimin 1, Vav1, Vav2, Dbs, members of the DOCK180 family,Kalirin-7, and Tiaml; G protein-coupled receptor kinase-interactingprotein 1 (GIT1), CIB1, filamin A, Etk/Bmx, and sphingosine.

Modulators of NMDA receptor include, but are not limited to,1-aminoadamantane, dextromethorphan, dextrorphan, ibogaine, ketamine,nitrous oxide, phencyclidine, riluzole, tiletamine, memantine,neramexane, dizocilpine, aptiganel, remacimide, 7-chlorokynurenate, DCKA(5,7-dichlorokynurenic acid), kynurenic acid,1-aminocyclopropanecarboxylic acid (ACPC), AP7(2-amino-7-phosphonoheptanoic acid), APV(R-2-amino-5-phosphonopentanoate), CPPene(3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid);(+)-(1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-pro-panol;(1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperi-dino)-1-propanol;(3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-)-chroman-4,7-diol;(1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluoro-phenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol-mesylate;and/or combinations thereof.

Modulators of estrogen receptors include, and are not limited to, PPT(4,4′,4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol); SKF-82958(6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine);estrogen; estradiol; estradiol derivatives, including but not limited to17-□ estradiol, estrone, estriol, ERβ-131, phytoestrogen, MK 101(bioNovo); VG-1010 (bioNovo); DPN (diarylpropiolitrile); ERB-041;WAY-202196; WAY-214156; genistein; estrogen; estradiol; estradiolderivatives, including but not limited to 17-β estradiol, estrone,estriol, benzopyrans and triazolo-tetrahydrofluorenones, disclosed inU.S. Pat. No. 7,279,499, and Parker et al., Bioorg. & Med. Chem. Ltrs.16: 4652-4656 (2006), each of which is incorporated herein by referencefor such disclosure.

Modulators of TrkB include by way of example, neutorophic factorsincluding BDNF and GDNF. Modulators of EphB include XL647 (Exelixis),EphB modulator compounds described in WO/2006081418 and US Appl. Pub.No. 20080300245, incorporated herein by reference for such disclosure,or the like.

Modulators of integrins include by way of example, ATN-161, PF-04605412,MEDI-522, Volociximab, natalizumab, Volociximab, Ro 27-2771, Ro 27-2441,etaracizumab, CNTO-95, JSM6427, cilengitide, R411 (Roche), EMD 121974,integrin antagonist compounds described in J. Med. Chem., 2002, 45 (16),pp 3451-3457, incorporated herein by reference for such disclosure, orthe like.

Adenosine receptor modulators include, by way of example, theophylline,8-Cyclopentyl-1,3-dimethylxanthine (CPX),8-Cyclopentyl-1,3-dipropylxanthine (DPCPX),8-Phenyl-1,3-dipropylxanthine, PSB 36, istradefylline, SCH-58261,SCH-442,416, ZM-241,385, CVT-6883, MRS-1706, MRS-1754, PSB-603,PSB-0788, PSB-1115, MRS-1191, MRS-1220, MRS-1334, MRS-1523, MRS-3777,MRE3008F20, PSB-10, PSB-11, VUF-5574, N6-Cyclopentyladenosine, CCPA,2′-MeCCPA, GR 79236, SDZ WAG 99, ATL-146e, CGS-21680, Regadenoson,5′-N-ethylcarboxamidoadenosine, BAY 60-6583, LUF-5835, LUF-5845,2-(1-Hexynyl)-N-methyladenosine, CF-101 (IB-MECA), 2-Cl-IB-MECA,CP-532,903, MRS-3558, Rosuvastatin, KW-3902, SLV320, mefloquine,regadenoson, or the like.

In some embodiments, compounds reducing PAK levels decrease PAKtranscription or translation or reduce RNA or protein levels. In someembodiments, a compound that decreases PAK levels is an upstreameffector of PAK. In some embodiments, a compound that decreases PAKlevels is an upstream effector of PAK. In some embodiments, exogenousexpression of the activated forms of the Rho family GTPases Chp andcdc42 in cells leads to increased activation of PAK while at the sametime increasing turnover of the PAK protein, significantly lowering itslevel in the cell (Hubsman et al. (2007) Biochem. J. 404: 487-497). PAKclearance agents include agents that increase expression of one or moreRho family GTPases and/or one or more guanine nucleotide exchangefactors (GEFs) that regulate the activity of Rho family GTPases, inwhich overexpression of a Rho family GTPase and/or a GEF results inlower levels of PAK protein in cells. PAK clearance agents also includeagonists of Rho family GTPases, as well as agonists of GTP exchangefactors that activate Rho family GTPases, such as but not limited toagonists of GEFs of the Dbl family that activate Rho family GTPases.

Overexpression of a Rho family GTPase is optionally by means ofintroducing a nucleic acid expression construct into the cells or byadministering a compound that induces transcription of the endogenousgene encoding the GTPase. In some embodiments, the Rho family GTPase isRac (e.g., Rac1, Rac2, or Rac3), cdc42, Chp, TC10, Tcl, or Wrnch-1. Forexample, a Rho family GTPase includes Rac1, Rac2, Rac3, or cdc42. A geneintroduced into cells that encodes a Rho family GTPase optionallyencodes a mutant form of the gene, for example, a more active form (forexample, a constitutively active form, Hubsman et al. (2007) Biochem. J.404: 487-497). In some embodiments, a PAK clearance agent is, forexample, a nucleic acid encoding a Rho family GTPase, in which the Rhofamily GTPase is expressed from a constitutive or inducible promoter.PAK levels in some embodiments are reduced by a compound that directlyor indirectly enhances expression of an endogenous gene encoding a Rhofamily GTPase.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a PAK clearance agent. A PAK clearanceagent in some embodiments is a Rho family GTPase agonist, or is acompound that directly or indirectly increases the activation level ofone or more Rho family GTPases. In some embodiments a PAK clearanceagent is a compound that increases the level of an activated Rho familyGTPase, such as, but not limited to, Rac or cdc42. The compound is, asnonlimiting examples, a compound that modifies a Rho family GTPase suchthat it is constitutively activated, or a compound that binds ormodifies a Rho family GTPase to increase the longevity or stability ofits activated (GTP bound) state. Activating mutations of Rho familyGTPases are known (Hubsman et al. (2007) Biochem. J. 404: 487-497), asare bacterial toxins such as E. coli necrotizing factors 1 and 2 (CNF1and CNF2) and Bordetella bronchiseptica dermonecrotizing toxin (DNT)that modify Rho family GTPases to cause their constitutive activation(Fiorentini et al. (2003) Cell Death and Differentiation 10:147-152).Toxins such as CNF1, CNF2, and DNT, fragments thereof that increase theactivity of a Rho family GTAPase, or peptides or polypeptides thatincrease the activity of a Rho family GTAPase having an amino acidsequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%, 96%, 97%,98%, 99%, or any other percent from about 80% to about 100% identical toa sequence of at least ten, at least twenty, at least thirty, at leastforty, at least fifty, at least sixty, at least seventy, at leasteighty, at least ninety, or at least 100 contiguous amino acids of thetoxin are also used as PAK clearance agents. Small molecule inhibitorsdesigned to mimic the effect of activating mutations of GTPases that areupstream regulators of PAK or designed to mimic the effect of bacterialtoxins that activate GTPases that bind and activate PAK are alsoincluded as compounds that downregulate PAK levels.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a compound that inhibitspost-translational modification of a Rho family GTPase. For example, insome embodiments a compound that inhibits prenylation of smallRho-family GTPases such as Rho, Rac, and cdc42 is used to increaseGTPase activity and thereby reduce the amount of PAK in the cell. Insome embodiments, a compound that decreases PAK levels is abisphosphonate compound that inhibits prenylation of Rho-family GTPasessuch as cdc42 and Rac, in which nonprenylated GTPases have higheractivity than their prenylated counterparts (Dunford et al. (2006) J.Bone Miner. Res. 21: 684-694; Reszka et al. (2004) Mini Rev. Med. Chem.4: 711-719).

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a compound that directly or indirectlydecreases the activation or activity of the upstream effectors of PAK.For example, in some embodiments a compound that inhibits the GTPaseactivity of the small Rho-family GTPases such as Rac and cdc42 therebyreduce the activation of PAK kinase. In some embodiments, the compoundthat decreases PAK activation is by secramine that inhibits cdc42activation, binding to membranes and GTP in the cell (Pelish et al.(2005) Nat. Chem. Biol. 2: 39-46). In some embodiments, PAK activationis decreased by EHT 1864, a small molecule that inhibits Rac1, Rac1b,Rac2 and Rac3 function by preventing binding to guanine nucleotideassociation and engagement with downstream effectors (Shutes et al.(2007) J. Biol. Chem. 49: 35666-35678). In some embodiments, PAKactivation is also decreased by the NSC23766 small molecule that bindsdirectly to Racl and prevents its activation by Rac-specific RhoGEFs(Gao et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101: 7618-7623). Insome embodiments, PAK activation is also decreased by the 16 kDafragment of prolactin (16 k PRL), generated from the cleavage of the 23kDa prolactin hormone by matrix metalloproteases and cathepsin D invarious tissues and cell types. 16 k PRL down-regulates theRas-Tiam1-Rac1-Pak1 signaling pathway by reducing Rac1 activation inresponse to cell stimuli such as wounding (Lee et al. (2007) Cancer Res67:11045-11053). In some embodiments, PAK activation is decreased byinhibition of NMDA and/or AMPA receptors. Examples of modulators of AMPAreceptors include and are not limited to ketamine, MK801, CNQX(6-cyano-7-nitroquinoxaline-2,3-dione); NBQX(2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione); DNQX(6,7-dinitroquinoxaline-2,3-dione); kynurenic acid;2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-[f]quinoxaline; PCP or the like.In some embodiments, PAK activation is decreased by inhibition of TrkBactivation. In some embodiments, PAK activation is decreased byinhibition of BDNF activation of TrkB. In some embodiments, compounds ofFormulae (I-X) are optionally administered in combination with anantibody to BDNF. In some embodiments, PAK activation is decreased byinhibition of TrkB receptors; NMDA receptors; EphB receptors; adenosinereceptors; estrogen receptors; integrins; Rho-family GTPases, includingCdc42, Rac (including but not limited to Rac1 and Rac2), CDK5, PI3kinases, NCK, PDK1, EKT, GRB2, Chp, TC10, Tcl, and Wrch-1; guaninenucleotide exchange factors (“GEFs”), such as but not limited to GEFT,members of the Dbl family of GEFs, p21-activated kinase interactingexchange factor (PIX), DEF6, Zizimin 1, Vav1, Vav2, Dbs, members of theDOCK180 family, Kalirin-7, and Tiam1; G protein-coupled receptorkinase-interacting protein 1 (GIT1), CIB1, filamin A, Etk/Bmx, and/orbinding to FMRP and/or sphingosine.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a compound that decreases PAK levels inthe cell, e.g., a compound that directly or indirectly increases theactivity of a guanine exchange factor (GEF) that promotes the activestate of a Rho family GTPase, such as an agonist of a GEF that activatesa Rho family GTPase, such as but not limited to, Rac or cdc42.Activation of GEFs is also effected by compounds that activate TrkB,NMDA, or EphB receptors.

In some embodiments, a PAK clearance agent is a nucleic acid encoding aGEF that activates a Rho family GTPase, in which the GEF is expressedfrom a constitutive or inducible promoter. In some embodiments, aguanine nucleotide exchange factor (GEF), such as but not limited to aGEF that activates a Rho family GTPase is overexpressed in cells toincrease the activation level of one or more Rho family GTPases andthereby lower the level of PAK in cells. GEFs include, for example,members of the Dbl family of GTPases, such as but not limited to, GEFT,PIX (e.g., alphaPIX, betaPIX), DEF6, Zizimin 1, Vav1, Vav2, Dbs, membersof the DOCK180 family, hPEM-2, FLJ00018, kalirin, Tiam1, STEF, DOCK2,DOCK6, DOCK7, DOCK9, Asf, EhGEF3, or GEF-1. In some embodiments, PAKlevels are also reduced by a compound that directly or indirectlyenhances expression of an endogenous gene encoding a GEF. A GEFexpressed from a nucleic acid construct introduced into cells is in someembodiments a mutant GEF, for example a mutant having enhanced activitywith respect to wild type.

The clearance agent is optionally a bacterial toxin such as Salmonellatyphinmurium toxin SpoE that acts as a GEF to promote Cdc42 nucleotideexchange (Buchwald et al. (2002) EMBO J. 21: 3286-3295; Schlumberger etal. (2003) J. Biological Chem. 278: 27149-27159). Toxins such as SopE,fragments thereof, or peptides or polypeptides having an amino acidsequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%, 96%, 97%,98%, 99%, or any other percent from about 80% to about 100% identical toa sequence of at least five, at least ten, at least twenty, at leastthirty, at least forty, at least fifty, at least sixty, at leastseventy, at least eighty, at least ninety, or at least 100 contiguousamino acids of the toxin are also optionally used as downregulators ofPAK activity. The toxin is optionally produced in cells from nucleicacid constructs introduced into cells.

Modulators of Upstream Regulators of PAKs

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a modulator of an upstream regulator ofPAKs. In some embodiments, a modulator of an upstream regulator of PAKsis an indirect inhibitor of PAK. In certain instances, a modulator of anupstream regulator of PAKs is a modulator of PDK1. In some instances, amodulator of PDK1 reduces of inhibits the activity of PDK1. In someinstances a PDK1 inhibitor is an antisense compound (e.g., any PDK1inhibitor described in U.S. Pat. No. 6,124,272, which PDK1 inhibitor isincorporated herein by reference). In some instances, a PDK1 inhibitoris a compound described in e.g., U.S. Pat. Nos. 7,344,870, and7,041,687, which PDK1 inhibitors are incorporated herein by reference.In some embodiments, an indirect inhibitor of PAK is a modulator of aPI3 kinase. In some instances a modulator of a PI3 kinase is a PI3kinase inhibitor. In some instances, a PI3 kinase inhibitor is anantisense compound (e.g., any PI3 kinase inhibitor described in WO2001/018023, which PI3 kinase inhibitors are incorporated herein byreference). In some instances, an inhibitor of a PI3 kinase is3-morpholino-5-phenylnaphthalen-1(4H)-one (LY294002), or a peptide basedcovalent conjugate of LY294002, (e.g., SF1126, Semaphorepharmaceuticals). In certain embodiments, an indirect inhibitor of PAKis a modulator of Cdc42. In certain embodiments, a modulator of Cdc42 isan inhibitor of Cdc42. In certain embodiments, a Cdc42 inhibitor is anantisense compound (e.g., any Cdc42 inhibitor described in U.S. Pat. No.6,410,323, which Cdc42 inhibitors are incorporated herein by reference).In some instances, an indirect inhibitor of PAK is a modulator of GRB2.In some instances, a modulator of GRB2 is an inhibitor of GRB2. In someinstances a GRB2 inhibitor is a GRb2 inhibitor described in e.g., U.S.Pat. No. 7,229,960, which GRB2 inhibitor is incorporated by referenceherein. In certain embodiments, an indirect inhibitor of PAK is amodulator of NCK. In certain embodiments, an indirect inhibitor of PAKis a modulator of ETK. In some instances, a modulator of ETK is aninhibitor of ETK. In some instances an ETK inhibitor is a compound e.g.,α-Cyano-(3,5-di-t-butyl-4-hydroxy)thiocinnamide (AG 879).

In some embodiments, indirect PAK inhibitors act by decreasingtranscription and/or translation of PAK. An indirect PAK inhibitor insome embodiments decreases transcription and/or translation of a PAK.For example, in some embodiments, modulation of PAK transcription ortranslation occurs through the administration of specific ornon-specific inhibitors of PAK transcription or translation. In someembodiments, proteins or non-protein factors that bind the upstreamregion of the PAK gene or the 5′ UTR of a PAK mRNA are assayed for theiraffect on transcription or translation using transcription andtranslation assays (see, for example, Baker, et al. (2003) J. Biol.Chem. 278: 17876-17884; Jiang et al. (2006) J. Chromatography A 1133:83-94; Novoa et al. (1997) Biochemistry 36: 7802-7809; Brandi et al.(2007) Methods Enzymol. 431: 229-267). PAK inhibitors include DNA or RNAbinding proteins or factors that reduce the level of transcription ortranslation or modified versions thereof. In other embodiments,compounds of Formulae (I-X) are optionally administered in combinationwith an agent that is a modified form (e.g., mutant form or chemicallymodified form) of a protein or other compound that positively regulatestranscription or translation of PAK, in which the modified form reducestranscription or translation of PAK. In yet other embodiments, atranscription or translation inhibitor is an antagonist of a protein orcompound that positively regulates transcription or translation of PAK,or is an agonist of a protein that represses transcription ortranslation.

Regions of a gene other than those upstream of the transcriptional startsite and regions of an mRNA other than the 5′ UTR (such as but notlimited to regions 3′ of the gene or in the 3′ UTR of an mRNA, orregions within intron sequences of either a gene or mRNA) also includesequences to which effectors of transcription, translation, mRNAprocessing, mRNA transport, and mRNA stability bind. In someembodiments, compounds of Formulae (I-X) are optionally administered incombination with a clearance agent comprising a polypeptide havinghomology to an endogenous protein that affects mRNA processing,transport, or stability, or is an antagonist or agonist of one or moreproteins that affect mRNA processing, transport, or turnover, such thatthe inhibitor reduces the expression of PAK protein by interfering withPAK mRNA transport or processing, or by reducing the half-life of PAKmRNA. A PAK clearance agents in some embodiments interferes withtransport or processing of a PAK mRNA, or by reducing the half-life of aPAK mRNA.

For example, PAK clearance agents decrease RNA and/or protein half-lifeof a PAK isoform, for example, by directly affecting mRNA and/or proteinstability. In certain embodiments, PAK clearance agents cause PAK mRNAand/or protein to be more accessible and/or susceptible to nucleases,proteases, and/or the proteasome. In some embodiments, compounds ofFormulae (I-X) are optionally administered in combination with agentsthat decrease the processing of PAK mRNA thereby reducing PAK activity.For example, PAK clearance agents function at the level of pre-mRNAsplicing, 5′ end formation (e.g. capping), 3′ end processing (e.g.cleavage and/or polyadenylation), nuclear export, and/or associationwith the translational machinery and/or ribosomes in the cytoplasm. Insome embodiments, PAK clearance agents cause a decrease in the level ofPAK mRNA and/or protein, the half-life of PAK mRNA and/or protein by atleast about 5%, at least about 10%, at least about 20%, at least about30%, at least about 40%, at least about 50%, at least about 60%, atleast about 80%, at least about 90%, at least about 95%, orsubstantially 100%.

In some embodiments, the clearance agent comprises one or more RNAi orantisense oligonucleotides directed against one or more PAK isoformRNAs. In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with agent that comprise one or moreribozymes directed against one or more PAK isoform RNAs. The design,synthesis, and use of RNAi constructs, antisense oligonucleotides, andribozymes are found, for example, in Dykxhoorn et al. (2003) Nat. Rev.Mol. Cell. Biol. 4: 457-467; Hannon et al. (2004) Nature 431: 371-378;Sarver et al. (1990) Science 247:1222-1225; Been et al. (1986) Cell47:207-216). In some embodiments, nucleic acid constructs that inducetriple helical structures are also introduced into cells to inhibittranscription of the PAK gene (Helene (1991) Anticancer Drug Des.6:569-584).

For example, a clearance agent is in some embodiments an RNAi moleculeor a nucleic acid construct that produces an RNAi molecule. An RNAimolecule comprises a double-stranded RNA of at least about seventeenbases having a 2-3 nucleotide single-stranded overhangs on each end ofthe double-stranded structure, in which one strand of thedouble-stranded RNA is substantially complementary to the target PAK RNAmolecule whose downregulation is desired. “Substantially complementary”means that one or more nucleotides within the double-stranded region arenot complementary to the opposite strand nucleotide(s). Tolerance ofmismatches is optionally assessed for individual RNAi structures basedon their ability to downregulate the target RNA or protein. In someembodiments, RNAi is introduced into the cells as one or more shorthairpin RNAs (“shRNAs”) or as one or more DNA constructs that aretranscribed to produce one or more shRNAs, in which the shRNAs areprocessed within the cell to produce one or more RNAi molecules.

Nucleic acid constructs for the expression of siRNA, shRNA, antisenseRNA, ribozymes, or nucleic acids for generating triple helicalstructures are optionally introduced as RNA molecules or as recombinantDNA constructs. DNA constructs for reducing gene expression areoptionally designed so that the desired RNA molecules are expressed inthe cell from a promoter that is transcriptionally active in mammaliancells, such as, for example, the SV40 promoter, the humancytomegalovirus immediate-early promoter (CMV promoter), or the pol IIIand/or pol II promoter using known methods. For some purposes, it isdesirable to use viral or plasmid-based nucleic acid constructs. Viralconstructs include but are not limited to retroviral constructs,lentiviral constructs, or based on a pox virus, a herpes simplex virus,an adenovirus, or an adeno-associated virus (AAV).

In other embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a polypeptide that decreases theactivity of PAK. Protein and peptide inhibitors of PAK are optionallybased on natural substrates of PAK, e.g., Myosin light chain kinase(MLCK), regulatory Myosin light chain (R-MLC), Myosins I heavy chain,myosin II heavy chain, Myosin VI, Caldesmon, Desmin, Op18/stathmin,Merlin, Filamin A, LIM kinase (LIMK), cortactin, cofilin, Ras, Raf, Mek,p47(phox), BAD, caspase 3, estrogen and/or progesterone receptors, NET1,Gaz, phosphoglycerate mutase-B, RhoGDI, prolactin, p41Arc, cortactinand/or Aurora-A. In some embodiments, compounds of Formulae (I-X) areoptionally administered in combination with an agent that is based on asequence of PAK itself, for example, the autoinhibitory domain in theN-terminal portion of the PAK protein that binds the catalytic domain ofa partner PAK molecule when the PAK molecule is in its homodimeric state(Zhao et al. (1998) Mol. Cell. Biol. 18:2153-2163; Knaus et al. (1998)J. Biol. Chem. 273: 21512-21518; Hofman et al. (2004) J. Cell Sci. 117:4343-4354). In some embodiments, polypeptide inhibitors of PAK comprisepeptide mimetics, in which the peptide has binding characteristicssimilar to a natural binding partner or substrate of PAK.

In some embodiments, provided herein are compounds that downregulate PAKprotein level. In some embodiments, the compounds described hereinactivate or increase the activity of an upstream regulator or downstreamtarget of PAK. In some embodiments, compounds described hereindownregulate protein level of a PAK. In some instances compoundsdescribed herein reduce at least one of the symptoms related aneuropsychiatric condition by reducing the amount of PAK in a cell. Insome embodiments a compound that decreases PAK protein levels in cellsalso decreases the activity of PAK in the cells. In some embodiments acompound that decreases PAK protein levels does not have a substantialimpact on PAK activity in cells. In some embodiments a compound thatincreases PAK activity in cells decreases PAK protein levels in thecells.

In some embodiments, a compound that decreases the amount of PAK proteinin cells decreases transcription and/or translation of PAK or increasesthe turnover rate of PAK mRNA or protein by modulating the activity ofan upstream effector or downstream regulator of PAK. In someembodiments, PAK expression or PAK levels are influenced by feedbackregulation based on the conformation, chemical modification, bindingstatus, or activity of PAK itself. In some embodiments, PAK expressionor PAK levels are influenced by feedback regulation based on theconformation, chemical modification, binding status, or activity ofmolecules directly or indirectly acted on by PAK signaling pathways. Asused herein “binding status” refers to any or a combination of whetherPAK, an upstream regulator of PAK, or a downstream effector of PAK is ina monomeric state or in an oligomeric complex with itself, or whether itis bound to other polypeptides or molecules. For example, a downstreamtarget of PAK, when phosphorylated by PAK, in some embodiments directlyor indirectly downregulates PAK expression or decrease the half-life ofPAK mRNA or protein. Downstream targets of PAK include but are notlimited to: Myosin light chain kinase (MLCK), regulatory Myosin lightchain (R-MLC), Myosins I heavy chain, myosin II heavy chain, Myosin VI,Caldesmon, Desmin, Op18/stathmin, Merlin, Filamin A, LIM kinase (LIMK),Ras, Raf, Mek, p47^(phox), BAD, caspase 3, estrogen and/or progesteronereceptors, NET1, Gaz, phosphoglycerate mutase-B, RhoGDI, prolactin,p41^(Arc), cortactin and/or Aurora-A. Downregulators of PAK levelsinclude downstream targets of PAK or fragments thereof in aphosphorylated state and downstream targets of PAK or fragments thereofin a hyperphosphorylated state.

A fragment of a downstream target of PAK includes any fragment with anamino acid sequence at least 80% to 100%, e.g., 85%, 90%, 92%, 93%, 95%,96%, 97%, 98%, 99%, or any other percent from about 80% to about 100%identical to a sequence of at least five, at least ten, at least twenty,at least thirty, at least forty, at least fifty, at least sixty, atleast seventy, at least eighty, at least ninety, or at least 100contiguous amino acids of the downstream regulator, in which thefragment of the downstream target of PAK is able to downregulate PAKmRNA or protein expression or increase turnover of PAK mRNA or protein.In some embodiments, the fragment of a downstream regulator of PAKcomprises a sequence that includes a phosphorylation site recognized byPAK, in which the site is phosphorylated.

In some embodiments, compounds of Formulae (I-X) are optionallyadministered in combination with a compound that decreases the level ofPAK including a peptide, polypeptide, or small molecule that inhibitsdephosphorylation of a downstream target of PAK, such thatphosphorylation of the downstream target remains at a level that leadsto downregulation of PAK levels.

In some embodiments, PAK activity is reduced or inhibited via activationand/or inhibition of an upstream regulator and/or downstream target ofPAK. In some embodiments, the protein expression of a PAK isdownregulated. In some embodiments, the amount of PAK in a cell isdecreased. In some embodiments a compound that decreases PAK proteinlevels in cells also decreases the activity of PAK in the cells. In someembodiments a compound that decreases PAK protein levels does notdecrease PAK activity in cells. In some embodiments a compound thatincreases PAK activity in cells decreases PAK protein levels in thecells.

In some instances, compounds of Formulae (I-X) are optionallyadministered in combination with a polypeptide that is delivered to oneor more brain regions of an individual by administration of a viralexpression vector, e.g., an AAV vector, a lentiviral vector, anadenoviral vector, or a HSV vector. A number of viral vectors fordelivery of therapeutic proteins are described in, e.g., U.S. Pat. Nos.,7,244,423, 6,780,409, 5,661,033. In some embodiments, the PAK inhibitorpolypeptide to be expressed is under the control of an induciblepromoter (e.g., a promoter containing a tet-operator). Inducible viralexpression vectors include, for example, those described in U.S. Pat.No. 6,953,575. Inducible expression of a PAK inhibitor polypeptideallows for tightly controlled and reversible increases of PAK inhibitorpolypeptide expression by varying the dose of an inducing agent (e.g.,tetracycline) administered to an individual.

Any combination of one or more PAK inhibitors and a second therapeuticagent is compatible with any method described herein. The PAK inhibitorcompositions described herein are also optionally used in combinationwith other therapeutic reagents that are selected for their therapeuticvalue for the condition to be treated. In general, the compositionsdescribed herein and, in embodiments where combinational therapy isemployed, other agents do not have to be administered in the samepharmaceutical composition, and, because of different physical andchemical characteristics, are optionally to administered by differentroutes. The initial administration is generally made according toestablished protocols, and then, based upon the observed effects, thedosage, modes of administration and times of administration subsequentlymodified.

In certain instances, it is appropriate to administer at least one PAKinhibitor composition described herein in combination with anothertherapeutic agent. By way of example only, if one of the side effectsexperienced by a patient upon receiving one of the PAK inhibitorcompositions described herein is nausea, then it is appropriate toadminister an anti-nausea agent in combination with the initialtherapeutic agent. Or, by way of example only, the therapeuticeffectiveness of a PAK inhibitor is enhanced by administration of anadjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit,but in combination with another therapeutic agent, the overalltherapeutic benefit to the patient is enhanced). Or, by way of exampleonly, the benefit experienced by a patient is increased by administeringa PAK inhibitor with another therapeutic agent (which also includes atherapeutic regimen) that also has therapeutic benefit. In any case,regardless of the disease, disorder or condition being treated, theoverall benefit experienced by the patient is either simply additive ofthe two therapeutic agents or the patient experiences a synergisticbenefit.

Therapeutically-effective dosages vary when the drugs are used intreatment combinations. Suitable methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents include,e.g., the use of metronomic dosing, i.e., providing more frequent, lowerdoses in order to minimize toxic side effects. Combination treatmentfurther includes periodic treatments that start and stop at varioustimes to assist with the clinical management of the patient.

In any case, the multiple therapeutic agents (one of which is a PAKinhibitor described herein) is administered in any order, or evensimultaneously. If simultaneously, the multiple therapeutic agents areoptionally provided in a single, unified form, or in multiple forms (byway of example only, either as a single pill or as two separate pills).In some embodiments, one of the therapeutic agents is given in multipledoses, or both are given as multiple doses. If not simultaneous, thetiming between the multiple doses optionally varies from more than zeroweeks to less than four weeks. In addition, the combination methods,compositions and formulations are not to be limited to the use of onlytwo agents; the use of multiple therapeutic combinations are alsoenvisioned.

The pharmaceutical agents which make up the combination therapydisclosed herein are optionally a combined dosage form or in separatedosage forms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy areoptionally also be administered sequentially, with either therapeuticcompound being administered by a regimen calling for two-stepadministration. The two-step administration regimen optionally calls forsequential administration of the active agents or spaced-apartadministration of the separate active agents. The time period betweenthe multiple administration steps ranges from, a few minutes to severalhours, depending upon the properties of each pharmaceutical agent, suchas potency, solubility, bioavailability, plasma half-life and kineticprofile of the pharmaceutical agent. Circadian variation of the targetmolecule concentration are optionally used to determine the optimal doseinterval.

In addition, a PAK inhibitor is optionally used in combination withprocedures that provide additional or synergistic benefit to thepatient. By way of example only, patients are expected to findtherapeutic and/or prophylactic benefit in the methods described herein,wherein pharmaceutical composition of a PAK inhibitor and/orcombinations with other therapeutics are combined with genetic testingto determine whether that individual is a carrier of a mutant gene thatis correlated with certain diseases or conditions.

A PAK inhibitor and the additional therapy(ies) are optionallyadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing aPAK inhibitor varies in some embodiments. Thus, for example, the PAKinhibitor is used as a prophylactic and administered continuously toindividuals with a propensity to develop conditions or diseases in orderto prevent the occurrence of the disease or condition. The PAKinhibitors and compositions are optionally administered to an individualduring or as soon as possible after the onset of the symptoms. Theadministration of the compounds are optionally initiated within thefirst 48 hours of the onset of the symptoms, preferably within the first48 hours of the onset of the symptoms, more preferably within the first6 hours of the onset of the symptoms, and most preferably within 3 hoursof the onset of the symptoms. The initial administration is optionallyvia any route practical, such as, for example, an intravenous injection,a bolus injection, infusion over 5 minutes to about 5 hours, a pill, acapsule, transdermal patch, buccal delivery, and the like, orcombination thereof. A PAK inhibitor is optionally administered as soonas is practicable after the onset of a disease or condition is detectedor suspected, and for a length of time necessary for the treatment ofthe disease, such as, for example, from about 1 month to about 3 months.The length of treatment optionally varies for each individual, and thelength is then determined using the known criteria. For example, the PAKinhibitor or a formulation containing the PAK inhibitor is administeredfor at least 2 weeks, preferably about 1 month to about 5 years, andmore preferably from about 1 month to about 3 years.

In some embodiments, the particular choice of compounds depends upon thediagnosis of the attending physicians and their judgment of thecondition of an individual and the appropriate treatment protocol. Thecompounds are optionally administered concurrently (e.g.,simultaneously, essentially simultaneously or within the same treatmentprotocol) or sequentially, depending upon the nature of the disease,disorder, or condition, the condition of an individual, and the actualchoice of compounds used. In certain instances, the determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is based on anevaluation of the disease being treated and the condition of anindividual.

In some embodiments, therapeutically-effective dosages vary when thedrugs are used in treatment combinations. Methods for experimentallydetermining therapeutically-effective dosages of drugs and other agentsfor use in combination treatment regimens are described in theliterature.

In some embodiments of the combination therapies described herein,dosages of the co-administered compounds vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein is optionally administered either simultaneously with thebiologically active agent(s), or sequentially. In certain instances, ifadministered sequentially, the attending physician will decide on theappropriate sequence of therapeutic compound described herein incombination with the additional therapeutic agent.

The multiple therapeutic agents (at least one of which is a therapeuticcompound described herein) are optionally administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsare optionally provided in a single, unified form, or in multiple forms(by way of example only, either as a single pill or as two separatepills). In certain instances, one of the therapeutic agents isoptionally given in multiple doses. In other instances, both areoptionally given as multiple doses. If not simultaneous, the timingbetween the multiple doses is any suitable timing, e.g., from more thanzero weeks to less than four weeks. In some embodiments, the additionaltherapeutic agent is utilized to achieve reversal or amelioration ofsymptoms of a neuropsychiatric condition, whereupon the therapeuticagent described herein (e.g., a compound of any one of Formulas I-X) issubsequently administered. In addition, the combination methods,compositions and formulations are not to be limited to the use of onlytwo agents; the use of multiple therapeutic combinations are alsoenvisioned (including two or more compounds described herein).

In certain embodiments, a dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors.

These factors include the disorder from which an individual suffers, aswell as the age, weight, sex, diet, and medical condition of anindividual. Thus, in various embodiments, the dosage regimen actuallyemployed varies and deviates from the dosage regimens set forth herein.

Examples of Pharmaceutical Compositions and Methods of Administration

Provided herein, in certain embodiments, are compositions comprising atherapeutically effective amount of any compound described herein (e.g.,a compound of Formula I-X).

Pharmaceutical compositions are formulated using one or morephysiologically acceptable carriers including excipients and auxiliarieswhich facilitate processing of the active compounds into preparationswhich are used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen. A summary of pharmaceuticalcompositions is found, for example, in Remington: The Science andPractice of Pharmacy, Nineteenth Ed (Ea hston, Pa.: Mack PublishingCompany, 1995); Hoover, John E., Remington's Pharmaceutical Sciences,Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L.,Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980;and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins, 1999).

Provided herein are pharmaceutical compositions that include one or morePAK inhibitors and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In addition, the PAK inhibitor isoptionally administered as pharmaceutical compositions in which it ismixed with other active ingredients, as in combination therapy. In someembodiments, the pharmaceutical compositions includes other medicinal orpharmaceutical agents, carriers, adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, and/or buffers. In addition, thepharmaceutical compositions also contain other therapeutically valuablesubstances.

A pharmaceutical composition, as used herein, refers to a mixture of aPAK inhibitor with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the PAK inhibitor to an organism. In practicing themethods of treatment or use provided herein, therapeutically effectiveamounts of a PAK inhibitor are administered in a pharmaceuticalcomposition to a mammal having a condition, disease, or disorder to betreated. Preferably, the mammal is a human. A therapeutically effectiveamount varies depending on the severity and stage of the condition, theage and relative health of an individual, the potency of the PAKinhibitor used and other factors. The PAK inhibitor is optionally usedsingly or in combination with one or more therapeutic agents ascomponents of mixtures.

The pharmaceutical formulations described herein are optionallyadministered to an individual by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular), intranasal, buccal, topical, rectal, ortransdermal administration routes. By way of example only, Example 131ais describes a parenteral formulation, Example 131f describes a rectalformulation. The pharmaceutical formulations described herein include,but are not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

The pharmaceutical compositions will include at least one PAK inhibitor,as an active ingredient in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these PAK inhibitors having the same type ofactivity. In some situations, PAK inhibitors exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. Additionally, the PAK inhibitor exists in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like. The solvated forms of the PAK inhibitorspresented herein are also considered to be disclosed herein.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility withcompounds disclosed herein, such as, a PAK inhibitor, and the releaseprofile properties of the desired dosage form. Exemplary carriermaterials include, e.g., binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, diluents, and the like.

Moreover, the pharmaceutical compositions described herein, whichinclude a PAK inhibitor, are formulated into any suitable dosage form,including but not limited to, aqueous oral dispersions, liquids, gels,syrups, elixirs, slurries, suspensions and the like, for oral ingestionby a patient to be treated, solid oral dosage forms, aerosols,controlled release formulations, fast melt formulations, effervescentformulations, lyophilized formulations, tablets, powders, pills,dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations. In some embodiments, a formulation comprising a PAKinhibitor is a solid drug dispersion. A solid dispersion is a dispersionof one or more active ingredients in an inert carrier or matrix at solidstate prepared by the melting (or fusion), solvent, or melting-solventmethods. (Chiou and Riegelman, Journal of Pharmaceutical Sciences, 60,1281 (1971)). The dispersion of one or more active agents in a soliddiluent is achieved without mechanical mixing. Solid dispersions arealso called solid-state dispersions. In some embodiments, any compounddescribed herein (e.g., a compound of Formula I-X) is formulated as aspray dried dispersion (SDD). An SDD is a single phase amorphousmolecular dispersion of a drug in a polymer matrix. It is a solidsolution prepared by dissolving the drug and a polymer in a solvent(e.g., acetone, methanol or the like) and spray drying the solution. Thesolvent rapidly evaporates from droplets which rapidly solidifies thepolymer and drug mixture trapping the drug in amorphous form as anamorphous molecular dispersion. In some embodiments, such amorphousdispersions are filled in capsules and/or constituted into oral powdersfor reconstitution. Solubility of an SDD comprising a drug is higherthan the solubility of a crystalline form of a drug or a non-SDDamorphous form of a drug. In some embodiments of the methods describedherein, PAK inhibitors are administered as SDDs constituted intoappropriate dosage forms described herein.

Pharmaceutical preparations for oral use are optionally obtained bymixing one or more solid excipient with a PAK inhibitor, optionallygrinding the resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients include, for example, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methylcellulose,microcrystalline cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP orpovidone) or calcium phosphate. If desired, disintegrating agents areadded, such as the cross linked croscarmellose sodium,polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions are generally used, which optionallycontain gum arabic, talc, polyvinylpyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments areoptionally added to the tablets or dragee coatings for identification orto characterize different combinations of active compound doses.

In some embodiments, the solid dosage forms disclosed herein are in theform of a tablet, (including a suspension tablet, a fast-melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. By way of example,Example 131b describes a solid dosage formulation that is a capsule. Inother embodiments, the pharmaceutical formulation is in the form of apowder. In still other embodiments, the pharmaceutical formulation is inthe form of a tablet, including but not limited to, a fast-melt tablet.Additionally, pharmaceutical formulations of a PAK inhibitor areoptionally administered as a single capsule or in multiple capsuledosage form. In some embodiments, the pharmaceutical formulation isadministered in two, or three, or four, capsules or tablets.

In another aspect, dosage forms include microencapsulated formulations.In some embodiments, one or more other compatible materials are presentin the microencapsulation material. Exemplary materials include, but arenot limited to, pH modifiers, erosion facilitators, anti-foaming agents,antioxidants, flavoring agents, and carrier materials such as binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, and diluents.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including a PAK inhibitor, include, but are notlimited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® orNisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a PAK inhibitor, are optionally furtherformulated to provide a controlled release of the PAK inhibitor.Controlled release refers to the release of the PAK inhibitor from adosage form in which it is incorporated according to a desired profileover an extended period of time. Controlled release profiles include,for example, sustained release, prolonged release, pulsatile release,and delayed release profiles. In contrast to immediate releasecompositions, controlled release compositions allow delivery of an agentto an individual over an extended period of time according to apredetermined profile. Such release rates provide therapeuticallyeffective levels of agent for an extended period of time and therebyprovide a longer period of pharmacologic response while minimizing sideeffects as compared to conventional rapid release dosage forms. Suchlonger periods of response provide for many inherent benefits that arenot achieved with the corresponding short acting, immediate releasepreparations.

In other embodiments, the formulations described herein, which include aPAK inhibitor, are delivered using a pulsatile dosage form. A pulsatiledosage form is capable of providing one or more immediate release pulsesat predetermined time points after a controlled lag time or at specificsites. Pulsatile dosage forms including the formulations describedherein, which include a PAK inhibitor, are optionally administered usinga variety of pulsatile formulations that include, but are not limitedto, those described in U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135,and 5,840,329. Other pulsatile release dosage forms suitable for usewith the present formulations include, but are not limited to, forexample, U.S. Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040,5,567,441 and 5,837,284.

Liquid formulation dosage forms for oral administration are optionallyaqueous suspensions selected from the group including, but not limitedto, pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition to the PAK inhibitor, the liquid dosage forms optionallyinclude additives, such as: (a) disintegrating agents; (b) dispersingagents; (c) wetting agents; (d) at least one preservative, (e) viscosityenhancing agents, (f) at least one sweetening agent, and (g) at leastone flavoring agent. In some embodiments, the aqueous dispersionsfurther includes a crystal-forming inhibitor.

In some embodiments, the pharmaceutical formulations described hereinare self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase isoptionally added just prior to administration, which ensures stabilityof an unstable or hydrophobic active ingredient. Thus, the SEDDSprovides an effective delivery system for oral and parenteral deliveryof hydrophobic active ingredients. In some embodiments, SEDDS providesimprovements in the bioavailability of hydrophobic active ingredients.Methods of producing self-emulsifying dosage forms include, but are notlimited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and6,960,563.

Suitable intranasal formulations include those described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Nasal dosageforms generally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents areoptionally present.

For administration by inhalation, the PAK inhibitor is optionally in aform as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit is determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator are formulated containing a powder mixof the PAK inhibitor and a suitable powder base such as lactose orstarch. By way of example, Example 131e describes an inhalationformulation.

Buccal formulations that include a PAK inhibitor include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136. In addition, the buccal dosage forms described hereinoptionally further include a bioerodible (hydrolysable) polymericcarrier that also serves to adhere the dosage form to the buccal mucosa.The buccal dosage form is fabricated so as to erode gradually over apredetermined time period, wherein the delivery of the PAK inhibitor, isprovided essentially throughout. Buccal drug delivery avoids thedisadvantages encountered with oral drug administration, e.g., slowabsorption, degradation of the active agent by fluids present in thegastrointestinal tract and/or first-pass inactivation in the liver. Thebioerodible (hydrolysable) polymeric carrier generally compriseshydrophilic (water-soluble and water-swellable) polymers that adhere tothe wet surface of the buccal mucosa. Examples of polymeric carriersuseful herein include acrylic acid polymers and co, e.g., those known as“carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is onesuch polymer). Other components also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions optionally take the form of tablets, lozenges, or gelsformulated in a conventional manner. By way of example, Examples 135cand 135d describe sublingual formulations.

Transdermal formulations of a PAK inhibitor are administered for exampleby those described in U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795,3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072,3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407,4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378,5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144. By way ofexample, Example 131g describes a topical formulation.

The transdermal formulations described herein include at least threecomponents: (1) a formulation of a PAK inhibitor; (2) a penetrationenhancer; and (3) an aqueous adjuvant. In addition, transdermalformulations include components such as, but not limited to, gellingagents, creams and ointment bases, and the like. In some embodiments,the transdermal formulation further includes a woven or non-wovenbacking material to enhance absorption and prevent the removal of thetransdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein maintain a saturated orsupersaturated state to promote diffusion into the skin.

In some embodiments, formulations suitable for transdermaladministration of a PAK inhibitor employ transdermal delivery devicesand transdermal delivery patches and are lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. Such patches are optionally constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. Stillfurther, transdermal delivery of the PAK inhibitor is optionallyaccomplished by means of iontophoretic patches and the like.Additionally, transdermal patches provide controlled delivery of the PAKinhibitor. The rate of absorption is optionally slowed by usingrate-controlling membranes or by trapping the PAK inhibitor within apolymer matrix or gel. Conversely, absorption enhancers are used toincrease absorption. An absorption enhancer or carrier includesabsorbable pharmaceutically acceptable solvents to assist passagethrough the skin. For example, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the PAKinhibitor optionally with carriers, optionally a rate controllingbarrier to deliver the PAK inhibitor to the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

Formulations that include a PAK inhibitor suitable for intramuscular,subcutaneous, or intravenous injection include physiologicallyacceptable sterile aqueous or non-aqueous solutions, dispersions,suspensions or emulsions, and sterile powders for reconstitution intosterile injectable solutions or dispersions. Examples of suitableaqueous and non-aqueous carriers, diluents, solvents, or vehiclesincluding water, ethanol, polyols (propyleneglycol, polyethylene-glycol,glycerol, cremophor and the like), suitable mixtures thereof, vegetableoils (such as olive oil) and injectable organic esters such as ethyloleate. Proper fluidity is maintained, for example, by the use of acoating such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.Formulations suitable for subcutaneous injection also contain optionaladditives such as preserving, wetting, emulsifying, and dispensingagents.

For intravenous injections, a PAK inhibitor is optionally formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hank's solution, Ringer's solution, or physiological saline buffer.For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. For other parenteralinjections, appropriate formulations include aqueous or nonaqueoussolutions, preferably with physiologically compatible buffers orexcipients.

Parenteral injections optionally involve bolus injection or continuousinfusion. Formulations for injection are optionally presented in unitdosage form, e.g., in ampoules or in multi dose containers, with anadded preservative. In some embodiments, the pharmaceutical compositiondescribed herein are in a form suitable for parenteral injection as asterile suspensions, solutions or emulsions in oily or aqueous vehicles,and contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Pharmaceutical formulations for parenteraladministration include aqueous solutions of the PAK inhibitor in watersoluble form. Additionally, suspensions of the PAK inhibitor areoptionally prepared as appropriate oily injection suspensions.

In some embodiments, the PAK inhibitor is administered topically andformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compositions optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

The PAK inhibitor is also optionally formulated in rectal compositionssuch as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Examples of Methods of Dosing and Treatment Regimens

The PAK inhibitor is optionally used in the preparation of medicamentsfor the prophylactic and/or therapeutic treatment of a neuropsychiatriccondition that would benefit, at least in part, from amelioration ofsymptoms. In addition, a method for treating any of the diseases orconditions described herein in an individual in need of such treatment,involves administration of pharmaceutical compositions containing atleast one PAK inhibitor described herein, or a pharmaceuticallyacceptable salt, pharmaceutically acceptable N-oxide, pharmaceuticallyactive metabolite, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said individual.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the PAK inhibitor isoptionally administered chronically, that is, for an extended period oftime, including throughout the duration of the patient's life in orderto ameliorate or otherwise control or limit the symptoms of thepatient's disease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the PAK inhibitor is optionally givencontinuously; alternatively, the dose of drug being administered istemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday optionallyvaries between 2 days and 1 year, including by way of example only, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days,20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350days, or 365 days. The dose reduction during a drug holiday includesfrom 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is reduced, as a function of thesymptoms, to a level at which the improved disease, disorder orcondition is retained. In some embodiments, patients requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

In some embodiments, the pharmaceutical compositions described hereinare in unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more PAK inhibitor. In someembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. In someembodiments, aqueous suspension compositions are packaged in single-dosenon-reclosable containers. Alternatively, multiple-dose reclosablecontainers are used, in which case it is typical to include apreservative in the composition. By way of example only, formulationsfor parenteral injection are presented in unit dosage form, whichinclude, but are not limited to ampoules, or in multi dose containers,with an added preservative.

The daily dosages appropriate for the PAK inhibitor are from about 0.01to 2.5 mg/kg per body weight. An indicated daily dosage in the largermammal, including, but not limited to, humans, is in the range fromabout 0.5 mg to about 1000 mg, conveniently administered in divideddoses, including, but not limited to, up to four times a day or inextended release form. Suitable unit dosage forms for oraladministration include from about 1 to 500 mg active ingredient, fromabout 1 to 250 mg of active ingredient, or from about 1 to about 100 mgactive ingredient. The foregoing ranges are merely suggestive, as thenumber of variables in regard to an individual treatment regime islarge, and considerable excursions from these recommended values are notuncommon. Such dosages are optionally altered depending on a number ofvariables, not limited to the activity of the PAK inhibitor used, thedisease or condition to be treated, the mode of administration, therequirements of an individual individual, the severity of the disease orcondition being treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens areoptionally determined in cell cultures or experimental animals,including, but not limited to, the determination of the LD50 (the doselethal to 50% of the population) and the ED50 (the dose therapeuticallyeffective in 50% of the population). The dose ratio between the toxicand therapeutic effects is the therapeutic index, which is expressed asthe ratio between LD50 and ED50. PAK inhibitors exhibiting hightherapeutic indices are preferred. The data obtained from cell cultureassays and animal studies is optionally used in formulating a range ofdosage for use in human. The dosage of such PAK inhibitors liespreferably within a range of circulating concentrations that include theED50 with minimal toxicity. The dosage optionally varies within thisrange depending upon the dosage form employed and the route ofadministration utilized.

Assays for Identification and Characterization of PAK Inhibitors

Small molecule PAK inhibitors are optionally identified inhigh-throughput in vitro or cellular assays as described in, e.g., Yu etal (2001), J Biochem (Tokyo); 129(2):243-251; Rininsland et al (2005),BMC Biotechnol, 5:16; and Allen et al (2006), ACS Chem Biol;1(6):371-376. PAK inhibitors suitable for the methods described hereinare available from a variety of sources including both natural (e.g.,plant extracts) and synthetic. For example, candidate PAK inhibitors areisolated from a combinatorial library, i.e., a collection of diversechemical compounds generated by either chemical synthesis or biologicalsynthesis by combining a number of chemical “building blocks.” Forexample, a linear combinatorial chemical library such as a polypeptidelibrary is formed by combining a set of chemical building blocks calledamino acids in every possible way for a given compound length (i.e., thenumber of amino acids in a polypeptide compound). Millions of chemicalcompounds can be synthesized through such combinatorial mixing ofchemical building blocks, as desired. Theoretically, the systematic,combinatorial mixing of 100 interchangeable chemical building blocksresults in the synthesis of 100 million tetrameric compounds or 10billion pentameric compounds. See Gallop et al. (1994), J. Med. Chem.37(9), 1233. Each member of a library may be singular and/or may be partof a mixture (e.g. a “compressed library”). The library may comprisepurified compounds and/or may be “dirty” (i.e., containing a quantity ofimpurities). Preparation and screening of combinatorial chemicallibraries are documented methodologies. See Cabilly, ed., Methods inMolecular Biology, Humana Press, Totowa, N.J., (1998). Combinatorialchemical libraries include, but are not limited to: diversomers such ashydantoins, benzodiazepines, and dipeptides, as described in, e.g.,Hobbs et al. (1993), Proc. Natl. Acad. Sci. U.S.A. 90, 6909; analogousorganic syntheses of small compound libraries, as described in Chen etal. (1994), J. Amer. Chem. Soc., 116: 2661; Oligocarbamates, asdescribed in Cho, et al. (1993), Science 261, 1303; peptidylphosphonates, as described in Campbell et al. (1994), J. Org. Chem., 59:658; and small organic molecule libraries containing, e.g.,thiazolidinones and metathiazanones (U.S. Pat. No. 5,549,974),pyrrolidines (U.S. Pat. Nos. 5,525,735 and 5,519,134), benzodiazepines(U.S. Pat. No. 5,288,514). In addition, numerous combinatorial librariesare commercially available from, e.g., ComGenex (Princeton, N.J.);Asinex (Moscow, Russia); Tripos, Inc. (St. Louis, Mo.); ChemStar, Ltd.(Moscow, Russia); 3D Pharmaceuticals (Exton, Pa.); and MartekBiosciences (Columbia, Md.).

Devices for the preparation of combinatorial libraries are commerciallyavailable (see, e.g., 357 MPS, 390 MPS from Advanced Chem Tech,Louisville, Ky.; Symphony from Rainin, Woburn, Mass.; 433A from AppliedBiosystems, Foster City, Calif.; and 9050 Plus from Millipore, Bedford,Mass.). A number of robotic systems have also been developed forsolution phase chemistries. These systems include automated workstationslike the automated synthesis apparatus developed by Takeda ChemicalIndustries, LTD (Osaka, Japan), and many robotic systems utilizingrobotic arms (Zymate II). Any of the above devices are optionally usedto generate combinatorial libraries for identification andcharacterization of PAK inhibitors which mimic the manual syntheticoperations performed by small molecule PAK inhibitors suitable for themethods described herein. Any of the above devices are optionally usedto identify and characterize small molecule PAK inhibitors suitable forthe methods disclosed herein. In many of the embodiments disclosedherein, PAK inhibitors, PAK binding molecules, and PAK clearance agentsare disclosed as polypeptides or proteins (where polypeptides comprisetwo or more amino acids). In these embodiments, the inventors alsocontemplate that PAK inhibitors, binding molecules, and clearance agentsalso include peptide mimetics based on the polypeptides, in which thepeptide mimetics interact with PAK or its upstream or downstreamregulators by replicating the binding or substrate interactionproperties of PAK or its regulators. Nucleic acid aptmers are alsocontemplated as PAK inhibitors, binding molecules, and clearance agents,as are small molecules other than peptides or nucleic acids. Forexample, in some embodiments small molecule PAK binding partners,inhibitors, or clearance agents, or small molecule agonists orantagonists of PAK modulators or targets, are designed or selected basedon analysis of the structure of PAK or its modulators or targets andbinding interactions with interacting molecules, using “rational drugdesign” (see, for example Jacobsen et al. (2004) Molecular Interventions4:337-347; Shi et al. (2007) Bioorg. Med. Chem. Lett. 17:6744-6749).

The identification of potential PAK inhibitors is determined by, forexample, assaying the in vitro kinase activity of PAK in the presence ofcandidate inhibitors. In such assays, PAK and/or a characteristic PAKfragment produced by recombinant means is contacted with a substrate inthe presence of a phosphate donor (e.g., ATP) containing radiolabeledphosphate, and PAK-dependent incorporation is measured. “Substrate”includes any substance containing a suitable hydroxyl moiety that canaccept the γ-phosphate group from a donor molecule such as ATP in areaction catalyzed by PAK. The substrate may be an endogenous substrateof PAK, i.e. a naturally occurring substance that is phosphorylated inunmodified cells by naturally-occurring PAK or any other substance thatis not normally phosphorylated by PAK in physiological conditions, butmay be phosphorylated in the employed conditions. The substrate may be aprotein or a peptide, and the phosphrylation reaction may occur on aserine and/or threonine residue of the substrate. For example, specificsubstrates, which are commonly employed in such assays include, but arenot limited to, histone proteins and myelin basic protein. In someembodiments, PAK inhibitors are identified using IMAP® technology.

Detection of PAK dependent phosphorylation of a substrate can bequantified by a number of means other than measurement of radiolabeledphosphate incorporation. For example, incorporation of phosphate groupsmay affect physiochemical properties of the substrate such aselectrophoretic mobility, chromatographic properties, light absorbance,fluorescence, and phosphorescence. Alternatively, monoclonal orpolyclonal antibodies can be generated which selectively recognizephosphorylated forms of the substrate from non-phosphorylated formswhereby allowing antibodies to function as an indicator of PAK kinaseactivity.

High-throughput PAK kinase assays can be performed in, for example,microtiter plates with each well containing PAK kinase or an activefragment thereof, substrate covalently linked to each well, P³²radiolabled ATP and a potential PAK inhibitor candidate. Microtiterplates can contain 96 wells or 1536 wells for large scale screening ofcombinatorial library compounds. After the phosphorylation reaction hascompleted, the plates are washed leaving the bound substrate. The platesare then detected for phosphate group incorporation via autoradiographyor antibody detection. Candidate PAK inhibitors are identified by theirability to decease the amount of PAK phosphotransferase ability upon asubstrate in comparison with PAK phosphotransferase ability alone.

The identification of potential PAK inhibitors may also be determined,for example, via in vitro competitive binding assays on the catalyticsites of PAK such as the ATP binding site and/or the substrate bindingsite. For binding assays on the ATP binding site, a known protein kinaseinhibitor with high affinity to the ATP binding site is used such asstaurosporine. Staurosporine is immobolized and may be fluorescentlylabeled, radiolabeled or in any manner that allows detection. Thelabeled staurosporine is introduced to recombinantly expressed PAKprotein or a fragment thereof along with potential PAK inhibitorcandidates. The candidate is tested for its ability to compete, in aconcentration-dependant manner, with the immobolized staurosporine forbinding to the PAK protein. The amount of staurosporine bound PAK isinversely proportional to the affinity of the candidate inhibitor forPAK. Potential inhibitors would decrease the quantifiable binding ofstaurosporine to PAK. See e.g., Fabian et al (2005) Nat. Biotech.,23:329. Candidates identified from this competitive binding assay forthe ATP binding site for PAK would then be further screened forselectivity against other kinases for PAK specificity.

The identification of potential PAK inhibitors may also be determined,for example, by in cyto assays of PAK activity in the presence of theinhibitor candidate. Various cell lines and tissues may be used,including cells specifically engineered for this purpose. In cytoscreening of inhibitor candidates may assay PAK activity by monitoringthe downstream effects of PAK activity. Such effects include, but arenot limited to, the formation of peripheral actin microspikes and orassociated loss of stress fibers as well as other cellular responsessuch as growth, growth arrest, differentiation, or apoptosis. See e.g.,Zhao et al., (1998) Mol. Cell. Biol. 18:2153. For example in a PAK yeastassay, yeast cells grow normally in glucose medium. Upon exposure togalactose however, intracellular PAK expression is induced, and in turn,the yeast cells die. Candidate compounds that inhibit PAK activity areidentified by their ability to prevent the yeast cells from dying fromPAK activation.

Alternatively, PAK-mediated phosphorylation of a downstream target ofPAK can be observed in cell based assays by first treating various celllines or tissues with PAK inhibitor candidates followed by lysis of thecells and detection of PAK mediated events. Cell lines used in thisexperiment may include cells specifically engineered for this purpose.PAK mediated events include, but are not limited to, PAK mediatedphosphorylation of downstream PAK mediators. For example,phosphorylation of downstream PAK mediators can be detected usingantibodies that specifically recognize the phosphorylated PAK mediatorbut not the unphosphorylated form. These antibodies have been describedin the literature and have been extensively used in kinase screeningcampaigns. In some instances a phospho LIMK antibody is used aftertreatment of HeLa cells stimulated with EGF or sphingosine to detectdownstream PAK signaling events.

The identification of potential PAK inhibitors may also be determined,for example, by in vivo assays involving the use of animal models,including transgenic animals that have been engineered to have specificdefects or carry markers that can be used to measure the ability of acandidate substance to reach and/or affect different cells within theorganism. For example, DISC1 knockout mice have defects in synapticplasticity and behavior from increased numbers of dendritic spines andan abundance of long and immature spines. Thus, identification of PAKinhibitors can comprise administering a candidate to DISC1 knockout miceand observing for reversals in synaptic plasticity and behavior defectsas a readout for PAK inhibition.

For example, fragile X mental retardation 1 (FMR1) knockout mice havedefects in synaptic plasticity and behavior from increased numbers ofdendritic spines and an abundance of long and immature spines. See e.g.,Comery et al., (1997) Proc. Natl. Acad. Sci. USA, 94:5401-04. As PAK isa downstream effector of the FMR1 gene, the defects are reversed uponthe use of dominant negative transgenes of PAK that inhibit endogenousPAK activity. See Hayashi et al. (2007) Proc. Natl. Acad. Sci. USA,104:11489-94. Thus, identification of PAK inhibitors can compriseadministering a candidate to FMR1 knockout mice and observing forreversals in synaptic plasticity and behavior defects as a readout forPAK inhibition.

For example, suitable animal models for Alzheimer's diseases areknock-ins or transgenes of the human mutated genes including transgenesof the “swedish” mutation of APP (APPswe), transgenes expressing themutant form of presenilin 1 and presenilin 2 found in familial/earlyonset AD. Thus, identification of PAK inhibitors can compriseadministering a candidate to a knock-in animal and observing forreversals in synaptic plasticity and behavior defects as a readout forPAK inhibition.

Administration of the candidate to the animal is via any clinical ornon-clinical route, including but not limited to oral, nasal, buccaland/or topical adiminstrations. Additionally or alternatively,administration may be intratracheal instillation, bronchialinstillation, intradermal, subcutaneous, intramuscular, intraperitoneal,inhalation, and/or intravenous injection.

Changes in spine morphology are detected using any suitable method,e.g., by use of 3D and/or 4D real time interactive imaging andvisualization. In some instances, the Imaris suite of products(available from Bitplane Scientific Solutions) provides functionalityfor visualization, segmentation and interpretation of 3D and 4Dmicroscopy datasets obtained from confocal and wide field microscopydata.

EXAMPLES

The following specific examples are to be construed as merelyillustrative, and not imitative of the remainder of the disclosure inany way whatsoever.

All synthetic chemistry was performed in standard laboratory glasswareunless indicated otherwise in the examples. Commercial reagents wereused as received. Analytical LC/MS was performed on an Agilent 1200system with a variable wavelength detector and Agilent 6140 Singlequadrupole mass spectrometer, alternating positive and negative ionscans. Retention times were determined from the extracted 220 nmchromatogram. ¹H NMR was performed on a Bruker DRX-400 at 400 MHz.Microwave reactions were performed in a Biotage Initiator using theinstrument software to control heating time and pressure. Hydrogenationreactions were performed on a H-Cube using the commercially availablecatalyst cartridges. Silica gel chromatography was performed manually.

Preparative HPLC was performed on a Waters 1525/2487 with UV detectionat 220 nm and manual collection.

Analytical LC/MS Method:

HPLC column: Zorbax SB-C18, 3.5 μm, 2.1 mm×30 mm, maintained at 40° C.HPLC Gradient: 0.4 mL/min, 95:5:0.1 water:acetonitrile:formic acid for0.1 min then to 5:95:0.1 water:acetonitrile:formic acid in 3.9 min,maintaining for 0.5 min.

Preparative HPLC Method:

HPLC column: Zorbax SB-C18 21.2×100 mm.HPLC Gradient: 20 mL/min, 95:5:0.1 water:methanol:formic acid to5:95:0.1water:methanol:formic acid; the gradient shape was optimized forindividual separations.

Example 1 Synthesis of8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Intermediate 1: Synthesis of 7-methoxy-1-aminoindane hydrochloride

Step 1: Synthesis of 7-methoxyindan-1-one oxime

To a suspension of 7-methoxyindanone (5.0 g, 31 mmol) and hydroxylaminehydrochloride (12.9 g, 185 mmol) in 100 mL ethanol was added thesolution of sodium acetate (11.4 g, 139 mmol) in 35 mL water at roomtemperature. The reaction mixture was heated at reflux for 4 h, thenstirred at room temperature for 18 h. The suspension was filtered, thewhite solid was washed with water, ethanol and diethyl ether to give thetitle compound (5.4 g, 31 mmol, 98%). ESMS m/z 178 (M+H)⁺.

Step 2: Synthesis of 7-methoxy-1-aminoindane hydrochloride

7-methoxyindan-1-one oxime (2.92 g, 16 mmol) was dissolved in aceticacid (150 mL) and hydrogenated on the H-Cube: 1 mL/min flow rate, 80°C., 100 bar with 10% Pd/C. The reaction mixture was evaporated, theresidue was dissolved in methanol and 1 equivalent of hydrochloric acidin methanol was added. The solvent was evaporated and the residue wastriturated with diethyl ether to give 7-methoxy-1-aminoindanehydrochloride (2.38 g, 12 mmol, 75%). ESMS m/z 147 (M+H)⁺.

Step 3: Synthesis of ethyl4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylate

To a stirred solution of ethyl4-chloro-2-methylthiopyrimidine-5-carboxylate (2.24 g, 9.62 mmol) in 35mL of anhydrous tetrahydrofuran was added triethylamine (4.00 mL, 2.90g, 28.72 mmol). The solution was cooled to 0-5° C. and7-methoxy-1-aminoindane hydrochloride (2.00 g, 10.01 mmol) was added.The reaction mixture was allowed to warm to room temperature and stirred48 h. The precipitate was filtered off, washed with ethyl acetate (1×25mL), and the combined filtrates were evaporated to dryness. The residuewas dissolved in dichloromethane (35 mL) washed with saturated sodiumbicarbonate solution (1×17 mL), dried over magnesium sulfate, filteredand concentrated to give4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylateas an oil (3.31 g, 9.21 mmol, 95%). ESMS m/z 360 (M+H)⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 8.63 (s, 1H), 8.43 (d, J=6.5 Hz, 1H), 7.21-7.26 (m,1H), 6.88 (d, J=7.5 Hz, 1H), 6.72 (d, J=8.3 Hz, 1H), 5.69-5.78 (m, 1H),4.26 (q, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.01-3.13 (m, 1H), 2.82-2.94 (m,1H), 2.59-2.67 (m, 1H), 2.56 (s, 3H), 2.04-2.14 (m, 1H), 1.33 (t, J=7.2Hz, 3H).

Step 4: Synthesis of(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)methanol

A solution of4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylate(3.25 g, 9.04 mmol) in anhydrous tetrahydrofuran (30 mL) was addeddropwise to a suspension of lithium aluminum hydride (0.54 g, 14.25mmol) in anhydrous tetrahydrofuran (8 mL) at 0-5° C. The reactionmixture was allowed to slowly warm to room temperature and stirred for18 h, then the mixture was cooled to 0-5° C. and quenched withwater:tetrahydrofuran (15 mL:5 mL), followed by a 10% sodium hydroxidesolution (11 mL). After stirring for 1 h, the precipitate was filteredoff and washed with ethyl acetate (5×25 mL). The combined filtrates werediluted with saturated brine solution (20 mL) and water (15 mL), the twophases were separated, and the organic layer was washed with water (1×25mL), dried over magnesium sulfate, filtered and evaporated to a lightbrown solid (2.43 g, 7.65 mmol, 84%). ESMS m/z 318 (M+H)⁺.

Step 5: Synthesis of4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carbaldehyde

To a solution of(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)methanol(2.36 g, 7.43 mmol) in dichloromethane (80 mL) was added manganesedioxide (90%, 3.87 g, 40 mmol) in small portions. The resultingsuspension was stirred for 18 h. Additional manganese dioxide (90%, 3.87g, 40 mmol) was added and the mixture was stirred for an additional 18h. The mixture was filtered through Celite and washed withdichloromethane (5×10 mL). The combined filtrates were evaporated invacuo to give4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carbaldehydeas a light brown solid (1.89 g, 5.99 mmol, 80%). ESMS m/z 316 (M+H)⁺.

Step 6: Synthesis of (E)-ethyl3-(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)acrylate

To a suspension of sodium hydride (60% dispersion, 0.21 g, 5.25 mmol) inanhydrous tetrahydrofuran (21 mL) was added dropwise a solution oftriethyl phosphonoacetate (1.03 mL, 1.16 g, 5.19 mmol) in anhydroustetrahydrofuran (5 mL) at 0-5° C. and the reaction mixture was stirredfor 30 min at this temperature. To this suspension was added carefully4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidine-5-carbaldehyde(1.48 g, 4.69 mmol) in anhydrous tetrahydrofuran (25 mL) below 5° C. Thereaction mixture was allowed to warm to room temperature and stirred for18 h. The mixture was cooled to below 5° C. and water (22 mL) was addeddropwise. It was diluted further with ethyl acetate (25 mL) andsaturated brine solution (15 mL), the two phases were separated, and theorganic layer was washed with saturated sodium carbonate solution (1×30mL), water (1×30 mL), dried over sodium sulfate, filtered and evaporatedto give (E)-ethyl3-(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)acrylateas a light brown solid (2.26 g, 5.86 mmol, quant.). ESMS m/z 386 (M+H)⁺;¹H NMR (400 MHz, CDCl₃), E/Z isomers in a ratio of 90:10, δ ppm 8.15 (s,0.9H, E), 8.13 (s, 0.1H, Z), 7.46 (d, J=16.e.g., 1 Hz, 0.9H, E),7.27-7.31 (m, 1H, E+Z), 6.92 (d, J=7.5 Hz, 1H, E+Z), 6.76 (d, J=8.3 Hz,0.9H, E), 6.73 (d, J=8.3 Hz, 0.1H, Z), 6.57 (d, J=11.8 Hz, 0.1H, Z) 6.27(d, J=16.e.g., 1 Hz, 0.9H, E), 5.98 (d, J=11.8 Hz, 0.1H, Z) 5.77 (d,J=4.5 Hz, 0.9H, E), 5.58-5.65 (m, 1H, E+Z), 5.17 (d, J=4.5 Hz, 0.1H, Z)4.23 (q, J=7.2 Hz, 2H, E+Z), 3.83 (s, 2.7H, E), 3.78 (s, 0.3H, Z),2.99-3.11 (m, 1H, E+Z), 2.85-2.95 (m, 1H, E+Z), 2.71-2.82 (m, 1H, E+Z),2.57 (s, 2.9H, E), 2.56 (s, 0.3H, Z) 1.99-2.11 (m, 1H, E+Z), 1.30 (t,J=7.2 Hz, 3H, E+Z).

Step 7: Synthesis of8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of (E)-ethyl3-(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)acrylate(0.30 g, 0.78 mmol) in N-methylpyrrolidinone (1.8 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL, 0.35 g, 2.29 mmol) and thereaction was stirred for 4 h at 120° C. The reaction mixture was pouredonto ice water and diluted with ethyl acetate (8 mL) and saturated brinesolution (2.5 mL). The two phases were separated, and the organic layerwas washed with 1 M hydrochloric acid (1×7 mL), water (1×7 mL), driedover sodium sulfate, filtered and evaporated to8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-oneas a brown oil (0.40 g, 1.18 mmol, quant.). ESMS m/z 340 (M+H)⁺.

Step 8: Synthesis of8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(0.32 g, 0.94 mmol) in dichloromethane (3 mL) was added3-chloroperbenzoic acid (70%, 0.18 g, 0.73 mmol) and the mixture wasstirred at room temperature for 5 h. The reaction mixture was extractedwith saturated sodium bicarbonate solution (2×1.5 mL), the organic layerwas dried over sodium sulfate, then filtered and evaporated to give8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-oneas a light brown oil (0.29 g, 0.82 mmol, 87%). ESMS m/z 356 (M+H)⁺.

Step 9: Synthesis of8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.29 g, 0.81 mmol) and 4-(4-methylpiperazino)aniline (0.15 g, 0.81mmol) were stirred at 140° C. for 4 h. The reaction mixture wasdissolved in dichloromethane (35 mL) and washed with 10% sodiumhydroxide solution (1×15 mL) then with water (1×15 mL). The organiclayer was dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel column chromatography usingdichloromethane:methanol (9:1) to give8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(32 mg, 0.07 mmol, 8.6%) as the major product. ESMS m/z 483 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ ppm 9.81 (br. s., 1H), 8.73 (s, 1H), 7.77 (d,J=9.3 Hz, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.14 (t, J=7.5 Hz, 1H), 6.89 (d,J=9.0 Hz, 2H), 6.87 (br.s., 1H), 6.84 (d, J=7.3 Hz, 1H), 6.65 (d, J=8.3Hz, 1H), 6.13 (d, J=9.3 Hz, 1H), 3.43 (s, 3H), 3.10-3.00 (m, 4H),3.00-2.85 (m, 2H), 2.45-2.38 (m, 4H), 2.35-2.25 (m, 2H), 2.20 (s, 3H).

Example 2-26

The following compounds were made by the method of Example 1 using theappropriate amine at Step 1 and aniline at Step 9. If necessary, theamine was synthesized by the method used for Intermediate 1. Compoundscontaining secondary amines on the aniline were synthesized using theappropriate Boc protected aminoaniline and in the final step weretreated with a solution of hydrogen chloride in an organic solvent toproduce the compound, optionally isolated as the hydrochloride salt.

No. Structure MW LCMS Ion Rt 2

404.5 405 1.87 3

391.5 392 2.64 4

349.4 350 2.68 5

392.5 393 2.48 6

466.6 467 2.88 7

452.6 453 2.82 8

494.5 495 2.89 9

494.5 495 2.75 10

480.5 481 2.84 11

466.6 467 2.90 12

466.6 467 2.91 13

495.5 496 3.66 14

508.5 509 2.92 15

495.5 496 2.95 16

468.6 469 2.74 17

470.6 471 2.76 18

452.6 453 2.92 19

466.6 465 2.97 20

483.6 484 2.34 21

494.6 495 3.31 22

456.5 457 3.11 23

470.6 471 3.15 24

486.6 487 3.19 25

487.0 487 3.20 26

498.6 499 3.36

Example 27 Synthesis of8-(2-bromobenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Step 1: Synthesis of8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a suspension of NaH (60%, 47 mg, 1.19 mmol) in anhydrousdimethylformamide (2 mL) was added2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg, 0.78 mmol,prepared by the method in example 1, Steps 1-5, using ammonia in thefirst step) at room temperature and stirred at 60° C. for 0.5 h. Thereaction mixture was cooled down to room temperature and 2-bromobenzylbromide was added and stirred for 48 h. The mixture was diluted withethyl acetate (20 mL) and 10% brine solution (10 mL), the two phaseswere separated, the aqueous layer was washed with ethyl acetate (1×20mL), the combined organic layer was dried over sodium sulfate, filteredand evaporated to give8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one, anorange oil (0.24 g, 0.66 mmol, 84%). ESMS m/z 362 (M+H)⁺; ¹H NMR (400MHz, CDCl₃) δ ppm 8.63 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.59 (dd, J=7.4,1.4 Hz, 1H), 7.05-7.15 (m, 2H), 6.74 (d, J=9.5 Hz, 1H), 6.65 (d, J=7.0Hz, 1H), 5.69 (s, 2H), 2.38 (s, 3H).

Step 2: Synthesis of8-(2-bromobenzyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.24g, 0.66 mmol) in methanol (20 mL) was added the solution of Oxone (720mg, 1.17 mmol) in water (10 mL). The mixture was stirred for 18 h, thenevaporated to dryness. The residue was dissolved in the mixture ofdichloromethane (20 mL) and water (20 mL), separated, and the aqueouslayer was extracted with dichloromethane (1×20 mL), and the combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuo to give8-(2-bromobenzyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one asa beige solid (0.17 g, 0.43 mmol, 65%). ESMS m/z 394 (M+H)⁺.

Step 3: Synthesis of8-(2-bromobenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

8-(2-bromobenzyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one(0.17 g, 0.43 mmol) and 4-(4-methylpiperazino)aniline (0.08 g, 0.43mmol) were stirred at 140° C. for 4 h. The reaction mixture wasdissolved in dichloromethane (20 mL) and washed with 10% sodiumhydroxide solution (1×10 mL) then with water (1×10 mL). The organiclayer was dried over sodium sulfate, filtered and evaporated. Theresidue was purified by silica gel column chromatography usingdichloromethane:methanol (95:5) and the product was recrystallized fromisopropanol to give the title compound (19 mg, 0.04 mmol, 9.3%). ESMSm/z 505 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.53 (s, 1H), 7.64 (dd,J=7.7, 1.4 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 7.06-7.25 (m, 5H), 6.82 (d,J=8.8 Hz, 2H), 6.66 (br. s., 1H), 6.54 (d, J=9.3 Hz, 1H), 5.59 (s, 2H),3.14-3.21 (m, 4H), 2.55-2.63 (m, 4H), 2.36 (s, 3H).

Example 28-80

The following compounds were made by the method of Example 30 using theappropriate benzyl bromide, benzyl chloride or phenethyl bromide at Step1 and aniline at Step 3. If necessary, the benzyl chloride was made byreduction of the appropriate acid or aldehyde to the alcohol followed byconversion to the benzyl chloride with thionyl chloride. Compoundscontaining secondary amines on the aniline were synthesized using theappropriate Boc protected aminoaniline and in the final step weretreated with a solution of hydrogen chloride in an organic solvent toproduce the compound, optionally isolated as the hydrochloride salt.

No. Structure MW LCMS Ion Rt 28

426.5 427 2.42 29

444.5 445 2.77 30

444.5 445 2.79 31

456.5 457 2.78 32

461.0 461 2.91 33

461.0 461 2.84 34

461.0 461 2.90 35

456.5 457 2.78 36

456.5 457 2.78 37

444.5 445 2.75 38

427.5 428 2.32 39

427.5 428 1.88 40

427.5 428 2.08 41

440.6 441 2.74 42

451.5 452 2.63 43

510.5 511 2.91 44

494.5 495 2.87 45

526.6 527 3.01 46

492.5 493 2.79 47

458.5 459 2.78 48

454.6 455 2.81 49

458.5 459 2.79 50

440.6 441 2.72 51

440.6 441 2.79 52

454.5 455 2.55 53

479.0 479 2.77 54

441.5 442 2.23 55

492.6 493 2.65 56

474.5 475 2.75 57

495.4 495 2.84 58

462.5 463 2.72 59

458.5 459 2.78 60

512.5 513 2.91 61

474.5 475 2.74 62

498.5 499 2.85 63

508.5 509 2.90 64

470.6 471 2.83 65

458.5 459 2.75 66

508.5 509 2.98 67

475.0 475 2.88 68

502.6 503 2.99 69

484.6 485 2.92 70

508.5 509 2.95 71

539.9 539 2.97 72

504.6 505 2.61 73

511.6 512 2.80 74

575.7 576 2.71 75

508.6 509 2.86 76

574.6 575 3.15 77

508.6 509 3.06 78

512.6 513 3.11 79

523.4 523 2.96 80

512.5 513 2.96

Example 81 Synthesis of8-(2-cyclopropylbenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Step 1: Synthesis of8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150mg, 0.41 mmol, Example 30), cyclopropylboronic acid (107 mg, 1.25 mmol),K₃PO₄ (264 mg, 1.24 mmol) and PdCl₂(Pcy₃)₂ (15 mg, 0.02 mmol) were mixedas solids and placed under argon. Argon was bubbled through a mixture oftoluene:water (20:1, 1.5 mL) for 20 min. The solvent was added to thesolid and the suspension was heated under microwave irradiation at 140°C. for 1.5 h. The reaction mixture was then diluted with toluene (10 mL)and water (1×5 mL), the two phases were separated, and the aqueous layerwas extracted with toluene (1×10 mL). The combined organic layers werewashed with water (1×10 mL) and evaporated to dryness. The crudecompound was purified by silica gel column chromatography usingdichloromethane:methanol (100:0.5) to yield8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-oneas an off-white solid (88 mg, 0.27 mmol, 66%). ESMS m/z 324 (M+H)⁺.

Step 2: Synthesis of8-(2-cyclopropylbenzyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of8-(2-cyclopropylbenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one(88 mg, 0.27 mmol) in dichloromethane (1 mL) was added3-chloroperbenzoic acid (70%, 67 mg, 0.27 mmol) at 0-5° C. and themixture was stirred at room temperature for 18 h. After completion, itwas diluted with dichloromethane (10 mL) and washed with saturatedsodium bicarbonate solution (1×5 mL) then with water (1×5 mL). Theorganic layer was dried over sodium sulfate, filtered and evaporated togive8-(2-cyclopropylbenzyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-oneas a pale yellow solid (80 mg, 0.23 mmol, 85%). ESMS m/z 340 (M+H)⁺.

Step 3: Synthesis of8-(2-cyclopropylbenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

8-(2-cyclopropylbenzyl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one(80 mg, 0.24 mmol) and 4-(4-methylpiperazino)aniline (45 mg, 0.24 mmol)were stirred at 140° C. for 3 h. After completion, the reaction mixturewas purified by silica gel column chromatography usingchloroform:methanol (100:3). The crude product was recrystallized fromacetonitrile to give the title compound (31 mg, 0.07 mmol, 29%). ESMSm/z 467 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.53 (s, 1H), 7.60 (d,J=9.3 Hz, 1H), 7.14-7.20 (m, 2H), 6.99-7.13 (m, 4H), 6.71 (br. s., 2H),6.63 (d, J=7.5 Hz, 1H), 6.54 (d, J=9.3 Hz, 1H), 5.72 (s, 2H), 3.12-3.18(m, 4H), 2.54-2.64 (m, 4H), 2.36 (s, 3H), 2.00-2.11 (m, 1H), 0.90-0.99(m, 2H), 0.69-0.77 (m, 2H).

Example 82-85

The following compounds were made by the method of Example 81 using theappropriate8-(2-bromobenzyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-onestarting material and boronic acid at Step 1 and aniline at Step 3.Compounds containing secondary amines on the aniline were synthesizedusing the appropriate Boc protected aminoaniline and in the final stepwere treated with a solution of hydrogen chloride in an organic solventto produce the compound, optionally isolated as the hydrochloride salt.

LCMS No. Structure MW Ion Rt 82

537.1 537 3.12 83

543.1 543 3.29 84

501.0 501 3.24 85

86

505.0 505 3.31 87

524.6 485 3.22

Examples 88-90

The following compounds were made by using the method of Example 81 Step1 as the last step starting with8-(2-Bromo-6-fluoro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-oneand the appropriate boronic acid.

LCMS No. Structure MW Ion Rt 88

520.6 521 3.26 89

526.6 527 3.28 90

484.6 485 3.22

Example 91 Synthesis of8-(2-fluoro-6-(methylthio)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Step 1: Synthesis of8-(2-fluoro-6-(methylthio)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

8-(2,6-difluorobenzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(23 mg, 0.05 mmol, Example 61) was treated with NaSMe (5 mg, 0.06 mmol)in DMSO (0.2 mL) at 100° C. for 2 h. The reaction mixture was dilutedwith water, the precipitated product was filtered off, then purified bysilica gel column chromatography using dichloromethane:methanol (95:5)to give8-(2-fluoro-6-(methylthio)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(22 mg, Y=90%). ESMS m/z 491 (M+H)⁺.

Example 92-93 Synthesis of8-(2-fluoro-6-(methylsulfinyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-oneand8-(2-fluoro-6-(methylsulfonyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

Step 1: Synthesis of8-(2-fluoro-6-(methylsulfinyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-oneand8-(2-fluoro-6-(methylsulfonyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one

8-(2-fluoro-6-(methylthio)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one(15 mg, 0.03 mmol, Example 94) was reacted with mCPBA (8 mg, 0.05 mmol)in dichloromethane (1 mL) for 2 hours at room temperature. It resultedin the mixture of8-(2-fluoro-6-(methylsulfinyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-oneand8-(2-fluoro-6-(methylsulfonyl)benzyl)-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one;they were separated by preparative HPLC to give (2.5 mg, Y=16%, ESMS m/z507 (M+H)⁺) and (1.1 mg; Y=7%, ESMS m/z 523 (M+H)⁺).

Example 94 Synthesis ofN-(5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-pyridin-2-yl)-ethane-1,2-diaminehydrochloride

Step 1: Synthesis of 1-(6-Chloro-pyridin-3-yl)-3-dimethylamino-propenone

5.00 g (32.2 mmol) 1-(6-Chloro-pyridin-3-yl)-ethanone was dissolved in40 mL dimethylformamide dimethylacetal, and stirred at 105° C. for 2 h.The solution was cooled to room temperature, and the yellow precipitatewas filtered to give 1-(6-Chloro-pyridin-3-yl)-3-dimethylamino-propenone(4.565 g, Y=67%) that was used without further purification.

Step 2: Synthesis of N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidinehydrochloride

10.00 g 4-(4-Methyl-piperazin-1-yl)-aniline (52 mmol) was dissolved in30 mL ethanol, 4.37 g cyanamide (104 mmol) and 7.3 mL of 65% nitric acid(114 mmol) were added. The reaction was stirred at 85° C. for 18 h undera nitrogen atmosphere. It was concentrated in vacuo, and the blackresidue was washed with isopropanol at reflux (3×25 mL). The solid wascooled to room temperature and ground under isopropanol in a ceramicmortar to give N-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidinehydrochloride (12.0 g, Y=77%) as a hygroscopic black powder.

Step 3: Synthesis of[4-(6-Chloro-pyridin-3-yl)-pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine

4.22 g 1-(6-Chloro-pyridin-3-yl)-3-dimethylamino-propenone (20 mmol) wasdissolved in 100 mL isopropanol, 5.92 gN-[4-(4-Methyl-piperazin-1-yl)-phenyl]-guanidine hydrochloride (20 mmol)and 0.96 g sodium hydroxide (24 mmol) were added and heated at refluxfor 18 h. The mixture was allowed to cool to room temperature andstirred at room temperature for three days. The yellow-green precipitatewas filtered to give[4-(6-Chloro-pyridin-3-yl)-pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine(2.50 g, Y=33%). Purity: 94% (LCMS); ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.49 (s, 1H), 9.14 (d, J=2.5 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.52 (dd,J=8.5, 2.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.41(d, J=5.3 Hz, 1H), 6.91 (d, J=9.0 Hz, 2H), 3.03-3.10 (m, 4H), 2.42-2.47(m, 4H), 2.22 (s, 3H).

Step 4: Synthesis ofN-(5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-pyridin-2-yl)-ethane-1,2-diamine

0.15 g (0.39 mmol) of[4-(6-Chloro-pyridin-3-yl)-pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-aminewas dissolved in 2.5 mL ethylenediamine and heated in a sealed tube at120° C. for 18 h. The reaction was cooled and evaporated to dryness andthe crude product was purified by silica gel column chromatography usingdichloromethane:methanol:triethylamine (9:1:0.05 to 1:1:0.05) to givethe title compound as a pale yellow solid (58 mg, 0.14 mmol, 36%). Theproduct was dissolved in dichloromethane (2 mL) then 0.51 M hydrochloricacid:diethyl ether (0.275 mL, 0.14 mmol) was added, it was stirred for0.5 h. The mixture was evaporated and the residue was suspended inmethanol and filtered to giveN-(5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-pyridin-2-yl)-ethane-1,2-diaminehydrochloride (35.5 mg, 0.08 mmol, 21%). ESMS m/z 405 (M+H)⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.36 (d,J=5.3 Hz, 1H), 8.15 (dd, J=8.8, 2.3 Hz, 1H), 7.87 (br. S., 3H), 7.62 (d,J=9.3 Hz, 2H), 7.33 (t, J=6.3 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 6.91 (d,J=9.3 Hz, 2H), 6.65 (d, J=8.5 Hz, 1H), 3.57 (q, J=6.3 Hz, 2H), 3.05-3.12(m, 4H), 3.01 (t, J=6.3 Hz, 2H), 2.46-2.49 (m, 4H), 2.25 (s, 3H).

Example 95-115

The following compounds were made by the method of Example 94 using theappropriate guanidine at Step 1, and the appropriate amine at Step 4.Example 110 was synthesized using (2-methylaminoethyl)-carbamic acidtert-butyl ester followed by deprotection with hydrochloric acid indiethyl ether.

LCMS No. Structure MW Ion Rt  95

396.5 397 2.12  96

393.5 394 0.93  97

380.9 381 2.78  98

418.5 419 1.10  99

474.6 475 2.10 100

472.6 473 2.19 101

432.6 433 1.29 102

433.6 434 2.17 103

487.7 488 1.14 104

417.6 418 2.45 105

403.5 404 2.24 106

418.5 419 2.16 107

486.7 487 2.32 108

361.5 362 2.31 109

389.5 390 2.17 110

418.5 419 2.11 111

390.5 391 0.83 112

404.5 405 3.44 113

422.5 423 2.02 114

418.5 419 1.35 115

432.5 433 2.23

Example 116 Synthesis of8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-onehydrochloride

Step 1: Synthesis of6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1.00 g,5.18 mmol) in anhydrous dimethylformamide (25 mL) was addedN-bromosuccinimide (0.99 g, 5.59 mmol) portionwise at room temperature,and the reaction mixture was stirred for 18 h. The mixture wasconcentrated, and the solid was triturated with hot water (1×20 mL),filtered, and washed with isopropanol to give title compound as a paleyellow solid (0.68 g, 2.50 mmol, 48%). ESMS m/z 272 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.88 (br. S., 1H), 8.84 (s, 1H), 8.47 (s, 1H), 2.57(s, 3H).

Step 2: Synthesis of6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

To a suspension of NaH (60%, 0.15 g, 3.75 mmol) in anhydrousdimethylformamide (10 mL) was added6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.68 g, 2.50mmol) at room temperature and the reaction was stirred at 50° C. for 0.5h. The reaction mixture was cooled down to room temperature and ethylbromide (0.22 mL, 0.32 g, 2.93 mmol) was added and stirred at 50° C. for1.5 h. After completion, the mixture was poured onto ice water (10 g),and the white precipitate was filtered off to give6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.57 g,1.90 mmol, 76%). ESMS m/z 300 (M+H)⁺.

Step 3: Synthesis of8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (150 mg,0.50 mmol), phenylboronic acid (183 mg, 1.50 mmol), K₃PO₄ (318 mg, 1.50mmol) and Pd(PPh₃)₄ (29 mg, 0.02 mmol) were mixed as solids and placedunder argon. Argon was bubbled through the mixture ofdimethoxyethane:ethanol:water (1:1:1, 2.0 mL) for 20 min. The solventwas added to the solid and the suspension was heated under microwaveirradiation at 120° C. for 1 h. After completion, the reaction mixtureevaporated to dryness, the crude product was purified by silica gelcolumn chromatography using dichloromethane:ethyl acetate (100:0.5) toyield 8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one asan off-white solid (121 mg, 0.41 mmol, 81%). ESMS m/z 298 (M+H)⁺; ¹H NMR(400 MHz, CDCl₃) δ ppm 8.59 (s, 1H), 8.03 (s, 1H), 4.55 (q, J=7.2 Hz,2H), 2.63 (s, 3H), 1.35 (t, J=7.2 Hz, 3H).

Step 4: Synthesis of8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of8-ethyl-2-(methylthio)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (127 mg,0.43 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzoic acid(70%, 95 mg, 0.38 mmol) at 0-5° C. and the mixture was stirred at roomtemperature for 18 h. The reaction was diluted with dichloromethane (5mL) and washed with saturated sodium bicarbonate solution (1×3 mL) thenwith water (1×3 mL). The organic layer was dried over sodium sulfate,filtered and evaporated to get8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one as apale yellow solid (120 mg, 0.38 mmol, 88%). ESMS m/z 314 (M+H)⁺.

Step 5: Synthesis of tert-butyl4-(4-(8-ethyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)-2-fluorophenyl)piperazine-1-carboxylate

8-ethyl-2-(methylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-one (120mg, 0.38 mmol) and 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylicacid tert-butyl ester (113 mg, 0.38 mmol) were stirred at 120° C. for 3h. The reaction mixture was purified by silica gel column chromatographyusing hexane:ethyl acetate (3:2). The isolated product wasrecrystallized from isopropanol to give the title compound (45 mg, 0.08mmol, 21%) as a pale yellow solid. ESMS m/z 545 (M+H)⁺.

Step 6: Synthesis of8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-onehydrochloride

To a stirred solution of tert-butyl4-(4-(8-ethyl-7-oxo-6-phenyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)-2-fluorophenyl)piperazine-1-carboxylate(45 mg, 0.08 mmol) in ethyl acetate (5 mL) was added a 4M solution ofhydrochloric acid in diethyl ether (5 mL) and the reaction was stirredfor 18 h. The precipitate was filtered off to give8-ethyl-2-(3-fluoro-4-(piperazin-1-yl)phenylamino)-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-onehydrochloride as an off-white solid (36 mg, 0.07 mmol, 87%). ESMS m/z445 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.21 (br. S., 1H), 9.22(br. S., 2H), 8.85 (s, 1H), 8.02 (s, 1H), 7.84 (d, J=15.e.g., 1 Hz, 1H),7.68 (d, J=7.5 Hz, 2H), 7.52 (d, J=8.5 Hz, 1H), 7.43 (t, J=7.3 Hz, 2H),7.37 (t, J=7.3 Hz, 1H), 7.11 (t, J=8.5 Hz, 1H), 4.41 (q, J=6.7 Hz, 2H),3.22 (br. S., 8H), 1.31 (t, J=6.7 Hz, 3H).

Example 117-118

The following compounds were made by the method of Example 120 using theappropriate boronic acid at Step 3 and aniline at Step 5.

LCMS No. Structure MW Ion Rt 117

513.4 513 3.62 118

440.6 441 3.32

Example 119-121

The following compounds were made by the methods of Example 1-26 usingthe appropriate phenylacetic acid ester at Step 6 in place of thephosphonoacetate ester.

LCMS No. Structure MW Ion Rt 119

570.6 571 3.46 120

556.6 557 3.37 121

570.6 571 3.49

Example 122 Synthesis of6-Bromo-8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one

8-(2-Fluoro-6-methylsulfanyl-benzyl)-2-(3-fluoro-4-piperazin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-onewas made by the method of Example 120 by reaction with4-{4-[8-(2,6-Difluoro-benzyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-2-fluoro-phenyl}-piperazine-1-carboxylicacid tert-butyl ester followed by removal of the Boc group by hydrogenchloride in ether in the final step.

Example 123 Identification of Compounds Having High Affinity for PAKActive Sites

A fluorescence-based assay format is used to determine IC50 values oftest compounds in vitro. Purified PAK kinase is incubated with ATP, anda test compound at various concentrations and a substrate peptidecontaining two fluorophores. In a second step, the reaction mix isincubated with a site-specific protease that cleaves non-phosphorylatedbut not phosphorylated substrate peptide, disrupting the FRET signalgenerated by the two fluorophores in the cleaved peptide (Z′Lyte™ Kinaseassay platform; Life Technologies).

Reagents: 50 mM HEPES, pH 7.5; 0.01% BRIJ-35; 10 mM MgCl₂; 1 mM EGTA, 2uM substrate peptide Ser/Thr20 (proprietary Life Technologies Sequence),PAK enzyme [2.42-30.8 ng for PAK1, 0.29-6 ng for PAK2, 1.5-20 ng forPAK3 and 0.1-0.86 ng for PAK4; actual enzyme amounts depend on lotactivity of the enzyme preparation]

Test compounds are dissolved in DMSO at various concentrations; thefinal DMSO concentration in the assay reaction is 1%.

ATP concentration at Km apparent is used in the assay [50 μM ATP forPAK1 assay, 75 μM ATP for PAK2 assay, 100 μM ATP for PAK3 assay, 5 μMATP for PAK-4 assay] in a total assay volume of 10 Assay reactions areincubated at room temperature for 1 hr. Following the kinase reaction, 5μl of 1:256 dilution of development solution A (Life Technologies) isadded and the reaction mix is incubated for an additional 1 hr at roomtemperature.

Plates are analyzed in a standard fluorescence plate reader (Tecan orequivalent) using an excitation wavelength of 400 nm and emissionwavelengths of 445 nm and 520 nm. Inhibition of kinase reaction isdetermined by

emission ratio=emission@445 nm/emission@520 nm

Based on these data, specific compounds have been identified that haverelatively high affinity for the catalytic domain of at least one PAKisoform, and are therefore useful inhibitors, as described herein.

TABLE 8 PAK1 PAK2 PAK3 PAK4 No. Structure IC50 μM IC50 μM IC50 μM IC50μM 1

B C C B 2

A B B B 3

C C B 4

C C B 5

B B B 6

B B B B 7

A B B B 8

A A A A 9

A A A A 10

A A A A 11

B B B B 12

A B B B 13

A A A A 14

A A A A 15

A A A A 16

B B B B 17

C C C C 18

A B B A 19

A A A A 20

C C C C 21

A A B B 22

A A B A 23

A A A A 27

A A A A 28

B B C 29

B B B 30

B C C 31

C C C 32

B C C 33

A A B 34

B C C 35

B C C 36

A B B 37

B B B 38

B C B 39

B C C 40

B C C 41

A A B 42

A A B 43

A A B 44

A A A A 45

A A A A 46

A A A A 47

B B B B 48

B B B B 49

A B C B 50

B B C B 51

A A B A 52

B B B B 53

A A A A 54

B B C B 55

A B B B 56

A B B B 57

A A B A 58

A B B B 59

A B B A 60

A A A A 61

A B B A 62

A A A A 63

A A A A 64

A A A B. 65

A A A A 66

A A B A 67

A B B A 68

A A A B 69

A A A A 70

B C C B 71

A A A A 72

A A A A 73

A A A A 74

A A A A 75

A B B B 76

B B B C 77

A A A B 78

A A A A 79

A A A A 80

A B B B 81

A A A A 82

B C C B 83

B C C C 84

A A A B 86

A A A B 91

A A A A 92

A B A B 94

A B B A 95

A B B A 96

B B B 97

B C C 98

A B B 99

B C B 100

B B C A 101

B B B 102

B C C 103

B C C 104

B B C A 105

B B B 106

A B B A 107

B B C A 108

B B C B 109

B C C A 110

B B C B 111

A B B A 112

B B C A 113

A B B A 114

C C C 115

C C C A 119

A A A C 120

A A A B 121

A A A B A: IC50 < 1 μM; B: IC50 > 1 μM and < 10 μM; C: IC50 > 10 μM

Example 124 Treatment of Schizophrenia by Administration of a PAKInhibitor Compound 84 in an Animal Model

The ability of a PAK inhibitor to ameliorate behavioral and anatomicalsymptoms of schizophrenia (i.e., their mouse analogs) is tested in adominant-negative DISC1 mouse model of schizophrenia (Hikida et al(2007), Proc Natl Acad Sci USA, 104(36):14501-14506).

Forty DISC1 mice (ages 5-8 months) on a C57BL6strain background aredivided into treatment group (1 mg/kg Compound 84, oral gavage) and aplacebo group (0.1% DMSO in physiological saline solution) and analyzedfor behavioral differences in open field, prepulse inhibition, andhidden food behavioral tests, with an interval of about one week betweeneach type of test. In the open field test, each mouse is placed in anovel open field box (40 cm×40 cm; San Diego Instruments, San Diego,Calif.) for two hours. Horizontal and vertical locomotor activities inthe periphery as well as the center area are automatically recorded byan infrared activity monitor (San Diego Instruments). Single breaks arereported as “counts.” In this behavioral test, a significant reductionin total activity in the treatment group relative to the placebo groupindicates a possible treatment effect.

In the hidden food test, mice are food-deprived for 24 h. Afterhabituation to a new cage for 5 min, a food pellet is hidden under thecage bedding. The time it takes for the mouse to find the food pellet ismeasured until a maximum of 10 min is reached. In this behavioral test,a significant reduction in time to find the food pellet in the treatmentgroup relative to the placebo group is indicative of a successfultreatment effect.

In the prepulse inhibition test, acoustic startle and prepulseinhibition responses are measured in a startle chamber (San DiegoInstruments). Each mouse is individualed to six sets of seven trailtypes distributed pseudorandomly: pulse-alone trials, prepulse-pulsetrials, and no-stimulus trials. The pulse used is 120 dB and theprepulse is 74 dB. A significant increase in the prepulse inhibitionresponse in the treatment group relative to the placebo group isindicative of a successful treatment effect.

In the forced swim test, each mouse is put in a large plastic cylinder,which is half-filled with room temperature water. The test duration is 6min, during which the swim/immobility times are recorded. In thisbehavioral test, a significant reduction in immobility in the treatmentgroup relative to the placebo group is indicative of a successfultreatment effect.

In order to evaluate the ability of Compound 84 to alter brainmorphology, an MRI study is conducted on placebo-treated and treatedgroups of DISC1-DN mice. In vivo MRI experiments are performed on an11.7T Bruker Biospec small animal imaging system. A three-dimensional,fast-spin echo, diffusion weighted (DW) imaging sequence with twinnavigation echoes is used to assess the ratio of lateral ventriclevolume to total brain volume. A decrease in this ratio in the treatedgroup relative to the ratio observed in the placebo-group is indicativeof a successful treatment effect.

Statistical Analysis. Statistical analysis is performed by ANOVA orrepeated ANOVA. Differences between groups are considered significant atp<0.05.

Example 125 In Vivo Monitoring of Dendritic Spine Plasticity in DoubleTransgenic GFP-M/DN-DISC1 Mice Treated with a PAK Inhibitor Compound 98

In the following experiment, dendritic spine plasticity is directlymonitored in vivo by two photon laser scanning microscopy (TPLSM) indouble transgenic GFP-M/DN-DISC1 mice treated with Compound 98 or aplacebo. Mice (C57BL/6) expressing GFP in a subset of cortical layer 5neurons (transgenic line GFP-M described in Feng et al, 2000, Neuron28:41-51) are crossed with DN-DISC1 C57BL/6 DN-DISC1 mice (Hikida et al(2007), Proc Natl Acad Sci USA, 104(36):14501-14506) to obtainheterozygous transgenic mice, which are then crossed to obtainhomozygous double transgenic GFPM/DN-DISC1 mice used in this study.

GFP-M/DN-DISC1 animals aged 28-61 d are anesthetized using avenin (16μl/g body weight; Sigma, St. Louis, Mo.). The skull is exposed,scrubbed, and cleaned with ethanol. Primary visual, somatosensory,auditory, and motor cortices are identified based on stereotaxiccoordinates, and their location is confirmed with tracer injections (seebelow).

Long-term imaging experiments are started at P40. The skull is thinnedover the imaging area as described in Grutzendler et al, (2002), Nature,420:812-816. A small metal bar is affixed to the skull. The metal bar isthen screwed into a plate that connected directly to the microscopestage for stability during imaging. The metal bar also allows formaintaining head angle and position during different imaging sessions.At the end of the imaging session, animals are sutured and returned totheir cage. Thirty animals previously imaged at P40 are then dividedinto a control group receiving a 1% sugar solution (oral gavage once perday) and a treatment group administered Compound 98, in 0.1% DMSO (oralgavage. 1 mg/kg, once per day). During the subsequent imaging sessions(at P45, P50, P55, or P70), animals are reanesthetized and the skull isrethinned. The same imaging area is identified based on the blood vesselpattern and gross dendritic pattern, which generally remains stable overthis time period.

At the end of the last imaging session, injections of cholera toxinsubunit B coupled to Alexa Fluor 594 are made adjacent to imaged areasto facilitate identification of imaged cells and cortical areas afterfixation. Mice are transcardially perfused and fixed withparaformaldehyde, and coronal sections are cut to verify the location ofimaged cells. Sections are then mounted in buffer, coverslipped, andsealed. Images are collected using a Fluoview confocal microscope(Olympus Optical, Melville, N.Y.).

For in vivo two photon imaging, a two-photon laser scanning microscopeis used as described in Majewska et al, (2000), pflügers Arch,441:398-408. The microscope consists of a modified Fluoview confocalscan head (Olympus Optical) and a titanium/sulphur laser providing 100fs pulses at 80 MHz at a wavelength of 920 nm (Tsunami; Spectra-Physics,Menlo Park, Calif.) pumped by a 10 W solid-state source (Millenia;Spectra-Physics). Fluorescence is detected using photomultiplier tubes(HC125-02; Hamamatsu, Shizouka, Japan) in whole-field detection mode.The craniotomy over the visual cortex is initially identified underwhole-field fluorescence illumination, and areas with superficialdendrites are identified using a 20×, 0.95 numerical aperture lens (IR2;Olympus Optical). Spiny dendrites are further identified under digitalzoom (7-10×) using two-photon imaging, and spines 50-200 μm below thepial surface are studied. Image acquisition is accomplished usingFluoview software. For motility measurements, Z stacks taken 0.5-1 μmapart are acquired every 5 min for 2 h. For synapse turnoverexperiments, Z stacks of dendrites and axons are acquired at P40 andthen again at P50 or P70. Dendrites and axons located in layers 1-3 arestudied. Although both layer 5 and layer 6 neurons are labeled in themice used in this study, only layer 5 neurons send a clear apicaldendrite close to the pial surface thus, the data will come from spineson the apical tuft of layer 5 neurons and axons in superficial corticallayers.

Images are exported to Matlab (Math Works, Natick, Mass.) in which theyare processed using custom-written algorithms for image enhancement andalignment of the time series. For motility measurements (see Majewska etal, (2003), Proc Nail Acad Sci USA, 100:16024-16029) spines are analyzedon two-dimensional projections containing between 5 and 30 individualimages; therefore, movements in the z dimension are not analyzed. Spinemotility is defined as the average change in length per unit time(micrometers per minute). Lengths are measured from the base of theprotrusion to its tip. The position of spines are compared on differentimaging days. Spines that are farther than 0.5 μm laterally from theirprevious location are considered to be different spines. Values forstable spines are defined as the percentage of the original spinepopulation present on the second day of imaging. Only areas that showhigh signal-to-noise ratio in all imaging sessions will be consideredfor analysis. Analysis is performed blind with respect to animal age andsensory cortical area. Spine motility (e.g., spine turnover),morphology, and density are then compared between control and treatmentgroups. It is expected that treatment with Compound 98 will rescuedefective spine morphology relative to that observed in untreatedcontrol animals.

Example 126 Treatment of Clinical Depression by Administration of a PAKInhibitor Compound 63 in an Animal Model

A rat olfactory bulbectomy (OBX) model of clinical depression (see,e.g., van Riezen et al (1990), Pharmacol Ther, 47(1):21-34; and Jarosiket al (2007), Exp Neurol, 204(1):20-28) is used to evaluate treatment ofclinical depression with Compound 63. Dendritic spine density andmorphology are compared in treated and untreated groups of animals asdescribed below. It is expected that treatment of OBX animals with a PAKinhibitor will cause an increase in spine density relative to thatobserved in untreated OBX animals.

All experiments are performed in strict accordance with NIH standardsfor laboratory animal use. The study uses 48 adult male Sprague-Dawleyrats (230-280 g) housed in groups of four animals (two sham and twoOBX), as indicated in van Riezen et al supra, in a controlledenvironment with food and water available ad libitum. Half of theexperimental animals (n=24) undergo bilateral olfactory bulbectomy (OBX)while the other half undergo sham surgery (n=24). Upon completion ofsurgery, animals are allowed to recover for 2 weeks prior to behavioraltesting. This is necessary to: 1) allow for the recovery of animal bodyweight which is reduced following surgery, 2) allow complete healing ofsuperficial surgical sites, and) “bulbectomy syndrome” develops duringthe first 2 weeks postsurgery.

Two weeks after surgery, OBX and sham-operated animals are subdividedinto one of four experimental conditions. One group of OBX animals isadministered daily injections of saline solution (n=6 for each surgicalcondition) or Compound 63 (1 mg/kg; oral gavage) (n=6 for each surgicalcondition). These groups are included to examine the effect of chronicadministration of Compound 63 (PAK inhibitor) on olfactory bulbectomizedanimals (2 weeks postsurgical recovery+2 weeks PAK inhibitor treatment).Administration of the drug or control solution are given at the sametime each day and in the home cage of each animal. Groups of OBX andsham-operated animals receive no treatment during this 2-week period andserve as unhandled controls. These groups are necessary to examine thepersistence of observed effects of OBX on dendritic spine density (4weeks postsurgery). Animals receiving postsurgery drug treatment aresacrificed 24 h after the last injection.

Animals are perfused transcardially with 4% formaldehyde (in 0.1 Msodium phosphate buffer, pH=7.4) under deep anesthesia with sodiumpentobarbital (60 mg/kg) at the completion of experimental procedures.Following fixation, brains are removed and placed in 4% formaldehyde(freshly depolymerized from para-formaldehyde) overnight. Brains arethen sectioned at 100 μm on a vibratome and prepared for Golgiimpregnation using a protocol adapted from previously described methods(Izzo et al, 1987). In brief, tissue sections are postfixed in 1% OsO4for 30 min and then washed in 0.1 M phosphate buffer (3×15 min).Sections are free-floated in 3.5% K2Cr2O7 solution for 90 min, mountedbetween two microscope slides in a “sandwich” assembly, and rapidlyimmersed in a 1% AgNO3 solution. The following day, sections are rinsedin ddH 20, dehydrated in 70% and 100% ethanol, cleared with Histoclear™,and mounted on microscope slides with DPX.

Dendritic spines are counted on 1250× camera lucida images that includeall spines observable in each focal plane occupied by the dendrite.Cells are analyzed only if they are fully impregnated (CA1: primaryapical dendrites extended into stratum lacunosum moleculare and basilardendrites extended into stratum oriens; CA3: primary apical dendritesextended into stratum lacunosum moleculare and basilar dendritesextended into stratum oriens; dentate gyrus: secondary dendritesextended from primary dendrite within the molecular layer), intact; andoccurring in regions of the section that are free of blood vessels,precipitate, and/or other imperfections. Dendritic spines are countedalong the entire length of secondary oblique dendritic processes (50-100μm) extending from the primary apical dendrite within stratum radiatumof area CA1 and CA3. In CA1 and CA3, secondary dendrites are defined asthose branches projecting directly from the primary apical dendriteexclusive of tertiary daughter branches. In addition, spines are countedalong the length of secondary dendrites of granule cells in the dentategyrus to determine if effects are limited to CA1 and CA3. In dentategyrus, secondary dendrites are analyzed in the glutamatergic entorhinalinput zone in the outer two-thirds of the molecular layer. Approximately20 dendritic segments (10 in each cerebral hemisphere; 50-100 μm inlength) in each hippocampal subregion (CA1, CA3, and dentate gyrus) areexamined for each experimental animal. Treatment conditions are codedthroughout the entire process of cell identification, spine counting,dendritic length analysis, and subsequent data analysis. Analysis ofvariance and Tukey post-hoc pairwise comparisons are used to assessdifferences between experimental groups.

When significant changes in dendritic spine density are observed, cameralucida images and the Zeiss CLSM measurement program are used toquantify the number and length of secondary dendrites. This analysis isnecessary as apparent changes in dendritic spine density can result froman increase or decrease in the length of dendrites and not the formationor loss of spines per se. Photomicrographs are obtained with ahelium-neon 633 laser and Zeiss 410 confocal laser scanning microscope.

Example 127 Treatment of Epilepsy by Administration of a PAK InhibitorCompound 12 in an Animal Model

A rat tetanus toxin model of epilepsy is used to evaluate treatment ofepilepsy with Compound 12.

Wistar rat pups (Harlan Sprague Dawley, Indianapolis, Ind.), 10 d ofage, are anesthetized with an intraperitoneal injection of ketamine andxylazine (33 and 1.5 mg/kg, respectively). When necessary, this issupplemented by inhalation of methoxyflurane (Metofane). Tetanus toxinsolution to be injected is generated by dissolving 2.5 or 5 ng oftetanus toxin in 20 or 40 n1 of sterile saline solution. Afterwards, thetetanus toxin solution is coinjected into the right hippocampus alongwith a solution of Compound 12.

To inject tetanus toxin and Compound 12, the pups are placed in aninfant rat stereotaxic head holder, a midline incision is made, and asmall hole is drilled in the skull. The stereotaxic coordinates forinjection are: anteroposterior, −2.1 mm; mediolateral, 3.0 mm from thebregma; and dorsoventral, −2.95 mm from the dural surface. The toxin andCompound 12 are slowly injected at 4 nl/min. After injection, the needleis left in place for 15 min to reduce reflux up the needle track. Duringinjections, the body temperature of rat pups is maintained by a warmed(electrically regulated) metal plate. Littermates, stereotaxicallyinjected with sterile saline, or untreated rats serve as controls.

The frequency of behavioral seizures is monitored for 1 hr/day for 10consecutive days after tetanus toxin/Compound 12 injections. The typesand duration of seizures are scored. Wild running seizures are mosteasily identified.

After seizure scoring on the 10th day animals are perfusedtranscardially and dendritic spines in the CA3 region are counted andanalyzed as described above.

The t test for comparison of two independent means is used in comparingthe number of seizures in treated vs untreated rats and in comparingdendritic and axon arbors in experimental and control rats. When dataare not normally distributed, a Mann-Whitney U test is used. Sigma Statis used to perform all statistical tests. It is expected that treatmentwith Compound 12 will reduce the frequency and severity of seizures.

Example 128 Clinical Trial: Treatment of Schizophrenia with a PAKInhibitor Compound 75

The following human clinical trial is performed to determine the safetyand efficacy of a PAK inhibitor compound for the treatment ofschizophrenia.

Sixty patients are recruited via referrals from community mental healthteams, after the patients have been diagnosed with schizophrenia usingthe Structured Clinical Interview for DSM-IV (“SCID”; First et al.,(1995), Structured Clinical Interview for DSM-IV Axis I Disorders,Patient Edition (SCID-P), version 2, New York State PsychiatricInstitute, Biometrics Research, New York).

A screening visit is arranged and a full explanation of the study priorto screening is provided if the patient appeared suitable for andinterested in taking part. For inclusion, all patients are required tomeet the following criteria: (i) aged between 18 and 60 years, (ii)receiving stable treatment with an atypical (Risperidone, Olanzapine,Quetiapine) antipsychotic and have stable psychotic symptoms (i.e. nochange in medication/dose of current medication over last 6 weeks andunlikely to require change in antipsychotic medication), (iii) negativeurine screening for illicit drugs and negative pregnancy test for femalepatients, (iv) cooperative, able to ingest oral medication and willingto undertake repeated cognitive testing, (v) able to provide writteninformed consent, (vi) reading ability of not more than 40 errors on theNational Adult Reading (Nelson et al, (1991)), and (vii) between 1 and 2standard deviations (S.D.) below expected performance on the basis ofage and education level on the California Verbal Learning Test (Delis etal., 1987). In addition, the following criteria are used to defineunsuitable patients: (i) concurrent DSM-IV diagnosis, (ii) currenttreatment with benzodiazepines or antidepressants, (iii) history ofneurodegenerative disorder in first degree relative (e.g. AD,Parkinson's disease, Huntington's disease, multiple sclerosis), (iv)history of DSM-IV substance dependence in the last year or substanceabuse within last month, (v) lifetime history of trauma resulting inloss of consciousness for 1 h or longer, (vi) participation in anotherinvestigational drug trial within 6 weeks prior to study entry, (vii)recent (within last 3 months) history of suicidal or violent acts, and(viii) current diagnosis of uncontrollable seizure disorder, activepeptic ulceration, severe and unstable cardiovascular disease or/andacute severe unstable asthma. The study procedures are approved by aninstitutional ethics review board. All patients in the study mustprovide written informed consent.

After screening has identified suitable patients that have providedinformed consent, patients are placed on a single-blind placebo for 1week. After 1 week on placebo (baseline), all patients complete acomprehensive cognitive test battery and undergo clinical assessments,and then are randomized into a double-blind protocol so that, half ofthe sample received Compound 75 capsules and the remaining half receivedplacebo for the next 24 weeks. Cognitive and clinical assessments arecarried out again at 12 weeks and 24 weeks.

Patients assigned to the treatment group will receive 1.5 mg twice a dayfor the first 2 weeks, 3 mg twice a day over the next 2 weeks, 4.5 mgtwice a day dose for the next 2 weeks and then 6 mg twice a day for theremaining period so at the time of 12 weeks cognitive assessments allpatients are on the maximum dose. The placebo group will receiveidentical appearing capsules containing ascorbic acid (100 mg).

Symptoms are rated within 4 days of cognitive testing using the Positiveand Negative Syndrome scale (PANSS) (Kay et al. (1987), Schizophr Res,13:261-276) on all three occasions. Side effects are also assessedwithin 4 days of testing using the Abnormal Involuntary Movement Scale(AIMS) (Guy, (1976), ECCDEU Assessment Manual for Psychopharmacology(revised), DHEW Publication No. (ADM)National Institutes of MentalHealth, Rockville, Md., pages 76-338). Inter-rater reliability iscarried out for PANSS at 6 monthly intervals by rating exemplar casesbased on patient interviews on videotapes.

The cognitive battery includes measures of executive functioning, verbalskills, verbal and spatial working memory, attention and psychomotorspeed. The battery is administered to all patients on all threeoccasions in the same fixed order (e.g., MATRICS cognitive battery, BACSscore, and performance in Wisconsin Card Sort Test). Patients areallowed to take breaks as needed in order to obtain maximal performanceat all times. Tests are administered and scored by trained psychologistswho are blind to patients' group affiliations and are not involved inpatients' treatment plan in any way.

Patients are told that the aim of the study is to investigate thecognitive effects of Compound 75. They are requested to abstain fromalcohol for at least 24 h prior to their scheduled cognitive testing.

The patients in the treatment and placebo groups are compared ondemographic, clinical, and cognitive variables obtained at baselineusing independent sample 1-tests.

The effects of Compound 75 on positive symptoms, negative symptoms,general psychopathology score, total PANSS scores, and the scores on theAIMS are analyzed (separately) by 2 (Treatment, placebo)×3 (Time:baseline, 12 weeks, 24 weeks) analysis of variance (ANOVA).

All cognitive variables are first examined for their distributionproperties, i.e., to ensure normality. The cognitive effects of Compound75 over time are then evaluated by Treatment×Time ANOVA, performedseparately for each variable, with Time as a within-individuals factorand Treatment as a between-individuals factor, followed by post-hoc meancomparisons wherever appropriate. All cognitive effects are thenre-evaluated using ANOVA performed separately on change scores computedfor each variable (12 weeks data minus baseline data, 24 weeks dataminus baseline data). Alpha level for testing significance of effects isp=0.05.

Example 129 Clinical Trial: Treatment of Epilepsy with a PAK1/PAK3Inhibitor

This is a 24-week study of an oral PAK1/PAK3 inhibitor in symptomaticpatients with a diagnosis of epilepsy. This is an open-label, single-armstudy to evaluate the dosing, tolerability, effectiveness and safety ofa PAK1/PAK3 inhibitor as initial therapy for epilepsy. A total of 30subjects will enrolled in the study.

Study Type: Interventional

Primary Outcome Measures:

Comparison of the mean stabilized dose of a PAK1/PAK3 inhibitor duringthe last 28 days of treatment between patients reporting 1 to 3 seizuresversus patients reporting more than 3 seizures, during the 3 monthsprior to study entry

Secondary Outcome Measures:

Influence of other patient characteristics on dose; Proportion ofsubjects remaining seizure-free; Time to stabilized dose; Reduction inseizure frequency.

Inclusion Criteria:

Subjects having new-onset epilepsy or epilepsy relapse characterized bypartial-onset seizures or primary generalized tonic-clonic seizures;Having at least 1 seizure within the 3 months prior to entry; Subjectswho are previously untreated for epilepsy, previously treated forepilepsy, or if currently taking epilepsy medication, must have beentaking it for less than 6 weeks

Exclusion Criteria:

Subjects currently on any medication for epilepsy for greater than 6weeks; Having active liver disease.

Experimental Design

Patients are divided into two groups, a placebo group and a PAK1/PAK3inhibitor group. Patients are administered tablets starting at 50milligrams per day and titrated to an individualized optimal dose, up toa maximum of 400 milligrams per day of the PAK1/PAK3 inhibitor by theend of week 6. Patients will take tablets by mouth twice a day (morningand evening) for 24 weeks. Changes to this schedule will be based on arisk-benefit assessment of the patient's clinical condition by theinvestigator, such as tolerability, or reaching a stable dose sufficientto control their seizures.

Patients are evaluated at weekly visits over a period of 6 weeks. Groupsare compared using ANOVA. Single variable differences are analyzed usingan independent samples t-test. A Pearson's coefficient is used todetermine relationship between seizure frequency and medication dose.

Example 130 Clinical Trial: Treatment of Alzheimer's Disease with a PAKInhibitor

The following human clinical trial is performed to determine the safetyand efficacy of the PAK inhibitor Compound 90 for the treatment ofAlzheimer's disease. The study aims to provide preliminary estimates ofeffect of administration of a PAK inhibitor (Compound 90) in delayingprogression of disease over a study period of one year.

Sixty patients between the ages of 55 and 80 are recruited via referralsfrom hospitals, after the patients have been diagnosed with mid stageAlzheimer's disease using the Mini-Mental State Exam scores and aclinical interview.

A screening visit is arranged and a full explanation of the study priorto screening is provided if the patient appeared suitable for andinterested in taking part. For inclusion, all patients are required tomeet the following criteria: (i) diagnosis of Alzheimer's disease (ii) astudy partner who can attend all study visits (iii) negative urinescreening for illicit drugs (iv) cooperative, able to ingest oralmedication and willing to undertake repeated cognitive testing, (v) ableto provide written informed consent. Exclusion criteria include (i)significant neurological disease other than Alzheimer's disease (ii)significant depression or other psychiatric disorder (iii) unstablemedical conditions. The study procedures are approved by aninstitutional ethics review board. All patients in the study mustprovide written informed consent.

After screening has identified suitable patients that have providedinformed consent, patients are placed on a single-blind placebo for 1week. After 1 week on placebo (baseline), all patients complete acomprehensive cognitive test battery and undergo clinical assessments,and then are randomized into a double-blind protocol so that, half ofthe sample received Compound 90 capsules and the remaining half receivedplacebo for the next 52 weeks. Cognitive and clinical assessments arecarried out again at 12 weeks, 26 weeks and 52 weeks.

Patients assigned to the Compound 90 group will receive a dose twice aday for 12 weeks at increasing doses. Cognitive assessments for allpatients are on the maximum dose. The placebo group will receiveidentical appearing capsules containing ascorbic acid (100 mg).

The cognitive battery includes measures of executive functioning, verbalskills, verbal and spatial working memory, attention and psychomotorspeed. The battery is administered to all patients on all threeoccasions in the same fixed order (e.g., Mini-Mental State Examination(MMSE), MATRICS cognitive battery, BACS score, and Alzheimer's diseaseAssessment Scale—Cognitive Subscale (ADAS-Cog)). Patients are allowed totake breaks as needed in order to obtain maximal performance at alltimes. Tests are administered and scored by trained psychologists whoare blind to patients' group affiliations and are not involved inpatients' treatment plan in any way. Alzheimer's disease CooperativeStudy-Activities of Daily Living (ADCS-ADL) is also recorded.

Patients are told that the aim of the study is to investigate thecognitive effects of Compound 90. They are requested to abstain fromalcohol for at least 24 h prior to their scheduled cognitive testing.

The patients in the Compound 90 and placebo groups are compared ondemographic, clinical, and cognitive variables obtained at baselineusing independent sample 1-tests.

The effects of Compound 90 on Neuropsychological Test Battery andNeuropsychiatric Inventory (NPI) are analyzed (separately) by 2(Treatment: Compound 90, placebo)×3 (Time: baseline, 12 weeks, 26 weeks,52 weeks) analysis of variance (ANOVA).

All cognitive variables are first examined for their distributionproperties, i.e., to ensure normality. The cognitive effects of Compound90 over time are then evaluated by Treatment×Time ANOVA, performedseparately for each variable, with Time as a within-individuals factorand Treatment as a between-individuals factor, followed by post-hoc meancomparisons wherever appropriate. All cognitive effects are thenre-evaluated using ANOVA performed separately on change scores computedfor each variable (12 weeks data minus baseline data, 26 weeks, 52 weeksdata minus baseline data). Alpha level for testing significance ofeffects is p=0.05.

Primary outcome measure is an improvement in (ADAS-Cog) scores.Secondary outcome measures are improvement in (MMSE) socres and(ADCS-ADL).

Example 131 Pharmaceutical Compositions Example 131a ParenteralComposition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula I-X is dissolved in DMSO and then mixed with 10 mLof 0.9% sterile saline. The mixture is incorporated into a dosage unitform suitable for administration by injection.

Example 131b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula I-X is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, e.g., a hard gelatin capsule,which is suitable for oral administration.

Example 131c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula I-X with 420 mg ofpowdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilledwater, and 0.42 mL mint extract. The mixture is gently blended andpoured into a mold to form a lozenge suitable for buccal administration.

Example 131d Fast-Disintegrating Sublingual Tablet

A fast-disintegrating sublingual tablet is prepared by mixing 48.5% byweigh of a compound of Formula I-X, 44.5% by weight of microcrystallinecellulose (KG-802), 5% by weight of low-substituted hydroxypropylcellulose (50 μm), and 2% by weight of magnesium stearate. Tablets areprepared by direct compression (AAPS PharmSciTech. 2006; 7(2):E41). Thetotal weight of the compressed tablets is maintained at 150 mg. Theformulation is prepared by mixing the amount of compound of Formula I-Xwith the total quantity of microcrystalline cellulose (MCC) andtwo-thirds of the quantity of low-substituted hydroxypropyl cellulose(L-HPC) by using a three dimensional manual mixer (Inversina®,Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesiumstearate (MS) and the remaining one-third of the quantity of L-HPC areadded 30 seconds before the end of mixing.

Example 131e Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula I-X is mixed with 50 mg of anhydrous citricacid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 131f Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula I-X is mixed with 2.5 g of methylcelluose (1500mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL of purifiedwater. The resulting gel mixture is then incorporated into rectaldelivery units, such as syringes, which are suitable for rectaladministration.

Example 131g Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula I-X is mixed with 1.75 g of hydroxypropyl celluose,10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL ofpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example 131h Ophthalmic Solution Composition

To prepare a pharmaceutical opthalmic solution composition, 100 mg of acompound of Formula I-X is mixed with 0.9 g of NaCl in 100 mL ofpurified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

Example 131i Nasal Spray Solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound ofFormula I-X is mixed with 30 mL of a 0.05M phosphate buffer solution (pH4.4). The solution is placed in a nasal administrator designed todeliver 100 μl of spray for each application.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1. A compound having the structure of Formula V or pharmaceuticallyacceptable salt or N-oxide thereof:

wherein: W is a bond; R⁶ is H, or halogen; R⁷ is H, halogen, CN, OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,—C(═O)N(R¹⁰)₂, CO₂R¹⁰, N(R¹⁰)₂, acyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; Q is substituted orunsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A issubstituted or unsubstituted aryl or heteroaryl substituted with 0-4 R⁴;each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹,—S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; R⁸ is H or substituted or unsubstituted alkyl; R⁹ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl each R¹⁰ is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, or two R¹⁰ together with the atoms to which they areattached form a heterocycle; ring B is aryl or heteroaryl substitutedwith R⁵; each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,—S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; r is 0-8; provided that when Q is unsubstitutedindane, tetrahydronaphthalene or fluorene, and R⁶ is H, ring B is notunsubstituted phenyl and R⁵ is not para substituted piperidinyl,pyrazolyl or methylpiperazinyl.
 2. The compound of claim 1, wherein thecompound of Formula V has the structure of Formula VI:

wherein: each of Y³, Y⁴ and Y⁵ are independently a bond, O, N—R^(1a),CR¹R², SO₂, or C═O; R^(1a) is H or substituted or unsubstituted alkyl;R¹ and R² are each independently H, halogen, —CN, —NO₂, —OH, —SR⁸,—S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)², —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; s is 0-4.
 3. The compound of claim 1, wherein thecompound of Formula V has the structure of Formula VII:

wherein: ring A is an aryl or heteroaryl substituted with R⁴; each R⁴ isindependently halogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹,—NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,—C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl; R⁸ is H orsubstituted or unsubstituted alkyl; R⁹ is substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; each R¹⁰is independently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroary, or two R¹⁰ together with thenitrogen to which they are attached form a heterocycle; each R¹¹ isindependently hydrogen, halogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹,—S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl; or two R¹¹together with the carbon atom to which they are attached form C═O; s is0-4; k is 1-4; z is 0 or 1; u is 1, 2 or 3; provided that z+u≠1; ring Bis an aryl or heteroaryl substituted with R⁵; each R⁵ is independentlyhalogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R⁹, —NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl; r is 0-8; R⁶ is H, orhalogen; R⁷ is H, halogen, CN, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂, CO₂R¹⁰, N(R¹⁰)₂,acyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.
 4. The compound of claim 2, wherein ring A is heteroarylring comprising 1-3 nitrogen atoms, an oxygen atom, a sulfur atom, orany combination thereof.
 5. The compound of claim 2, wherein ring A is aphenyl ring.
 6. The compound of claim 3, wherein the compound of FormulaVII has a structure of Formula VIIA, Formula VIIB, Formula VIIC, FormulaVIID, Formula VIIE, Formula VIIF, Formula VIIG or Formula VIIH:


7. The compound of claim 6, wherein R¹¹ is H, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy or N(R¹⁰)₂. 8.The compound of claim 6, wherein R¹¹ is H.
 9. The compound of claim 6,wherein each R⁴ is independently halogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl.
 10. Thecompound of claim 9, wherein each R⁴ is independently Cl, F, CF₃ or OMe.11. A compound having the structure of Formula VIII or pharmaceuticallyacceptable salt or N-oxide thereof:

W is a bond; R⁶ is H, halogen, —CN, —OH, substituted or unsubstitutedalkoxy, —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁷ is H, halogen, —CN, —OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,—C(═O)N(R¹⁰)₂, —CO₂R¹⁰, —N(R¹⁰)₂, acyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; Q is

R¹ is H or substituted or unsubstituted alkyl; R² is substituted orunsubstituted alkyl, or R¹ and R² together with the carbon to which theyare attached form a C₃-C₆ cycloalkyl ring; p is 1, 2 or 3; ring A isaryl substituted with R⁴; each R⁴ is independently halogen, —CN, —NO₂,—OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸, S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl; R⁸ is H or substituted orunsubstituted alkyl; R⁹ is substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl or substituted or unsubstituted heteroaryl each R¹⁰ isindependently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, or two R¹⁰ together with theatoms to which they are attached form a heterocycle; s is 0-4; ring B isaryl or heteroaryl substituted with R⁵; each R⁵ is independentlyhalogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl; r is 0-8; provided thatwhen s is zero, then R² is not methyl.
 12. The compound of claim 11wherein W is a bond; R⁶ is H, halogen, —CN, —OH, substituted orunsubstituted alkoxy, —N(R¹⁰)₂, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; R⁷ is H,halogen, —CN, —OH, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, —C(═O)N(R¹⁰)₂, —CO₂R¹⁰, —N(R¹⁰)₂, acyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl; Q is

R¹ is H or substituted or unsubstituted alkyl; R² is substituted orunsubstituted alkyl, or R¹ and R² together with the carbon to which theyare attached form a C₃-C₆ cycloalkyl ring; p is 1, 2 or 3; ring A isaryl substituted with R³ and R⁴; R³ is halogen, —CN, —NO₂, —OH, —OCF₃,—OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂,—C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R⁹,NR¹⁰C(═O)OR⁹, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl; each R⁴ is independently halogen, —CN,—NO₂, —OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹,—NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂,—C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl or substituted or unsubstituted heterocycloalkyl; R⁸ is H orsubstituted or unsubstituted alkyl; R⁹ is substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl each R¹⁰is independently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, or two R¹⁰ together with theatoms to which they are attached form a heterocycle; s is 0-4; ring B isaryl or heteroaryl substituted with R⁵; each R⁵ is independentlyhalogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl; r is 0-8.
 13. Thecompound of claim 12, wherein R³ is halogen, —CN, —NO₂, —OH, —OCF₃,—OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl.
 14. The compound of claim 12, wherein Qis


15. The compound of claim 11, wherein the compound of Formula VIII hasthe structure of Formula VIIIA or Formula VIIIB:


16. The compound of claim 11, wherein the compound of Formula VIII hasthe structure of Formula (IX):

wherein: R¹ is H or substituted or unsubstituted alkyl; R² issubstituted or unsubstituted alkyl; and R³ is halogen, alkyl,fluoroalkyl, alkoxy, fluoroalkoxy, SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl,
 17. The compound of claim 16, wherein R³ is F, Cl,SCF₃, CF₃, OMe, (R) or (S)—S(═O)R⁹ or —S(O)₂R⁹.
 18. The compound ofclaim 16, wherein the compound of Formula IX has the structure ofFormula (IXA) or Formula (IXB):


19. A compound having the structure of Formula X or pharmaceuticallyacceptable salt or N-oxide thereof:

wherein: W is a bond; R⁶ is H, halogen, —CN, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, —N(R¹⁰)₂,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁷ is H, halogen, —CN, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂,—CO₂R¹⁰, —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; Q is

R¹ and R² are each independently H or substituted or unsubstitutedalkyl; or R¹ and R² together with the carbon to which they are attachedform a C₃-C₆ cycloalkyl ring; p is 1, 2 or 3; ring A is aryl substitutedwith R³ and R⁴; R³ is a substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl attached to ring A via a carbon atom; each R⁴ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸,—S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; R⁸ is H or substituted or unsubstituted alkyl; R⁹ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl each R¹⁰ is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, or two R¹⁰ together with the atoms to which they areattached form a heterocycle; s is 0-4; ring B is aryl or heteroarylsubstituted with R⁵; each R⁵ is independently halogen, —CN, —NO₂, —OH,—SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,—NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl; r is 0-8.
 20. The compound of claim 19wherein Q is:


21. The compound of claim 19, wherein Q is


22. The compound of claim 19, wherein R³ is a C₃-C₆ cycloalkyl ring, a5-6-membered heteroaryl ring comprising 1-3 nitrogen atoms, an oxygenatom, a sulfur atom, or any combination thereof, or a 3-6-memberedheterocycloalkyl ring comprising 1-3 nitrogen atoms, an oxygen atom, asulfur atom, or any combination thereof, that is attached to ring via acarbon atom and wherein R³ is further substituted by halogen, cyano,alkyl, alkoxy, —SR⁸, (R) or (S)—S(O)R⁹ or —S(O)₂R⁹.
 23. The compound ofclaim 22, wherein R¹ and R² are H.
 24. A method for treating aneuropsychiatric condition comprising administering to an individual inneed thereof a therapeutically effective amount of a compound of FormulaVA or pharmaceutically acceptable salt or N-oxide thereof:

wherein: W is a bond; R⁶ is H, or halogen; R⁷ is H, halogen, CN, OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,—C(═O)N(R¹⁰)₂, CO₂R¹⁰, N(R¹⁰)₂, acyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; Q is substituted orunsubstituted cycloalkyl or heterocycloalkyl fused to ring A; ring A issubstituted or unsubstituted aryl or heteroaryl substituted with 0-4 R⁴;each R⁴ is independently halogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹,—S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰,—N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; R⁸ is H or substituted or unsubstituted alkyl; R⁹ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl each R¹⁰ is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, or two R¹⁰ together with the atoms to which they areattached form a heterocycle; ring B is aryl or heteroaryl substitutedwith R⁵; each R⁵ is independently halogen, —CN, —NO₂, —OH, —SR⁸,—S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; and r is 0-8.
 25. A method for treating aneuropsychiatric condition comprising administering to an individual inneed thereof a therapeutically effective amount of a compound of FormulaVIIIC or pharmaceutically acceptable salt or N-oxide thereof:

W is a bond; R⁶ is H, halogen, —CN, —OH, substituted or unsubstitutedalkoxy, —N(R¹⁰)₂, substituted or unsubstituted heteroalkyl, substitutedor unsubstituted cycloalkyl; substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; R⁷ is H, halogen, —CN, —OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,—C(═O)N(R¹⁰)₂, —CO₂R¹⁰, —N(R¹⁰)₂, acyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; Q is

R¹ is H or substituted or unsubstituted alkyl; R² is substituted orunsubstituted alkyl, or R¹ and R² together with the carbon to which theyare attached form a C₃-C₆ cycloalkyl ring; p is 1, 2 or 3; ring A isaryl substituted with R⁴; each R⁴ is independently halogen, —CN, —NO₂,—OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl; R⁸ is H or substituted orunsubstituted alkyl; R⁹ is substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl or substituted or unsubstituted heteroaryl each R¹⁰ isindependently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl, or two R¹⁰ together with theatoms to which they are attached form a heterocycle; s is 0-4; ring B isaryl or heteroaryl substituted with R⁵; each R⁵ is independentlyhalogen, —CN, —NO₂, —OH, —SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹,—S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂,—NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl; and r is 0-8.
 26. Amethod for treating a neuropsychiatric condition comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a compound of Formula X or pharmaceuticallyacceptable salt or N-oxide thereof:

wherein: W is a bond; R⁶ is H, halogen, —CN, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, —N(R¹⁰)₂,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; R⁷ is H, halogen, —CN, —OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, —C(═O)N(R¹⁰)₂,—CO₂R¹⁰, —N(R¹⁰)₂, acyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; Q is

R¹ and R² are each independently H or substituted or unsubstitutedalkyl; or R¹ and R² together with the carbon to which they are attachedform a C₃-C₆ cycloalkyl ring; p is 1, 2 or 3; ring A is aryl substitutedwith R³ and R⁴; R³ is a substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl attached to ring A via a carbon atom; each R⁴ isindependently halogen, —CN, —NO₂, —OH, —OCF₃, —OCF₂H, —CF₃, —SR⁸,—S(═O)R⁹, —S(═O)₂R⁹, —NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹, —OC(═O)R⁹,—CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰, —NR¹⁰C(═O)OR¹⁰,—NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; R⁸ is H or substituted or unsubstituted alkyl; R⁹ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl each R¹⁰ is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl, or two R¹⁰ together with the atoms to which they areattached form a heterocycle; s is 0-4; ring B is aryl or heteroarylsubstituted with R⁵; each R⁵ is independently halogen, —CN, —NO₂, —OH,—SR⁸, —S(═O)R⁹, —S(═O)₂R⁹, NR¹⁰S(═O)₂R⁹, —S(═O)₂N(R¹⁰)₂, —C(═O)R⁹,—OC(═O)R⁹, —CO₂R¹⁰, —N(R¹⁰)₂, —C(═O)N(R¹⁰)₂, —NR¹⁰C(═O)R¹⁰,—NR¹⁰C(═O)OR¹⁰, —NR¹⁰C(═O)N(R¹⁰)₂, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl or substituted orunsubstituted heterocycloalkyl; r is 0-8.
 27. The method of claim 24,wherein the compound is a p21-activated kinase inhibitor.
 28. The methodof claim 27, wherein administration of a therapeutically effectiveamount of the p21-activated kinase inhibitor causes substantiallycomplete inhibition of one or more Group I p21-activated kinases. 29.The method of claim 27, wherein administration of a therapeuticallyeffective amount of the p21-activated kinase inhibitor causes partialinhibition of one or more Group I p21-activated kinases.
 30. The methodof claim 27, wherein the p21-activated kinase inhibitor modulatesdendritic spine morphology or synaptic function.
 31. The method of claim30, wherein the p21-activated kinase inhibitor modulates dendritic spinedensity.
 32. The method of claim 30, wherein the p21-activated kinaseinhibitor modulates dendritic spine length.
 33. The method of claim 30,wherein the p21-activated kinase inhibitor modulates dendritic spineneck diameter.
 34. The method of claim 30, wherein the p21-activatedkinase inhibitor normalizes or partially normalizes aberrant synapticplasticity associated with a neuropsychiatric condition.
 35. The methodof claim 30, wherein the p21-activated kinase inhibitor normalizes orpartially normalizes aberrant long term depression (LTD) associated witha neuropsychiatric condition.
 36. The method of claim 30, wherein thep21-activated kinase inhibitor normalizes or partially normalizesaberrant long term potentiation (LTP) associated with a neuropsychiatriccondition.